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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Burkholderia cepacia complex infection'. | Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.
BACKGROUND
Burkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.
METHODS
We retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.
RESULTS
The most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.
CONCLUSIONS
B. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.
Background
Burkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.
Materials and methods
This single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.
Results
Table 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).
Table 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis
No. Age/
sex Year Risk factors Prior use
of cortico-
steroid Location
, size Hypopyon Corneal perforation Treatment Surgery Presenting
VA Final
VA Other isolates
1 71/f 2003 Diabetic mellitus − C, L + − Ceftazidime, Vancomycin − NLP NLP
2 52/m 2007 Ocular trauma + C, S + − Ceftazidime, Sulfamethoxazole/Trimethoprim AMT CF CF Candida parapsilosis
3 64/f 2010 Diabetic mellitus, Recent ocular surgery (PKP) + C, L − − Ceftazidime AMT, patch graft, evisceration NLP NLP
4 71/m 2010 HZV keratitis − C, L − + Amikacin, Vancomycin, Sulfamethoxazole/Trimethoprim − NLP NLP Serratia marcescens
5 24/m 2010 HSV keratitis + PC, L − − Ceftazidime, acyclovir − CF 20/200
6 57/f 2014 HSV keratitis − C, L − + Levofloxacin, acyclovir Patch graft, PKP HM LP
7 85/m 2016 Unknown − C, L + − Amikacin, voriconazole − HM HM Fusarium solani
8 53/m 2016 Ocular trauma + PC, M + + Ceftazidime, Moxifloxacin (oral), Vancomycin 20/200 20/70
9 84/f 2017 Ocular surface problem − PC, S − − Levofloxacin − CF CF
10 50/f 2017 Contact lens wear − PC, S − − Levofloxacin − 20/25 20/50
11 88/f 2017 Recent ocular surgery (PKP, AMT) + C, M + − Levofloxacin AMT HM 20/1000 Pseudomonas aeruginosa
12 60/m 2017 Unknown − C, L + − Levofloxacin AMT, keratectomy, tarsorrhaphy, patch graft CF NA
13 84/f 2018 HSV keratitis + PC, S + + Ceftazidime − HM CF
14 65/f 2018 Diabetic mellitus, Recurrent ocular ulcer + PC, M + − Levofloxacin − HM NLP Corynebacterium propinquum, Corynebacterium species
15 48/m 2018 Ocular trauma − PC, S − − Levofloxacin − 20/50 20/30 Bacillus megaterium,
Arthrobacter species
16 69/f 2019 Unknown − C, L − − Levofloxacin − NLP NLP Pseudomonas aeruginosa
17 36/m 2019 HZV keratitis, Contact lens wear + C, M − − Levofloxacin − CF 20/400
AMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity
Of the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.
Predisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.
Of the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.
All patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.
Visual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.
Case report (Patient 13)
An 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.
Fig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon
Discussion
B. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.
Table 2 Clinical data of the patients with Burkholderia capecia keratitis
Age/sex Risk factor Prior steroid use Location, size Hypopyon Medical treatment Surgery Presenting VA Final VA Other isolates\
Matoba et al. [7] 59/m HSV keratitis + C, M - Levofloxacin - CF 20/200 Enterococcus species, Staphylococcus aureus
Lin et al. [5] 16/f Ortho-keratology lens – PC, S – Ciprofloxacin – 20/40 20/20 Pseudomonas putida, Pseudomonas aeruginosa.
Ornek et al. [18]a 78/f Cataract surgery + C, M – Ciprofloxacin +IVI
Ceftazidime
– NLP NA
Chaurasia et al. [4] NA Unknown + NA, M – Ciprofloxacin Tissue adhesive LP NA
NA Unknown – NA, S + Ciprofloxacin – NA NA
NA Trauma – NA, L + Ciprofloxacin TPK LP NA
NA TPK + NA, S – Ceftazidime – HM NA
Reddy et al. [9] 27/m LASIK + C, multiple infiltrates + Tobramycin and Gatifloxacin CF 20/20
C central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty
a A case of keratitis and endophthalmitis
In our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.
In our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.
B. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).
The visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.
The retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.
In conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.
Abbreviation
VAVisual acuity
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Authors’ contributions
All authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.
Consent for publication
The consent for publication of biometric data from Patient 13 was obtained.
Competing interests
The authors declare that they have no competing interests. | ACYCLOVIR, PREDNISOLONE ACETATE | DrugsGivenReaction | CC BY | 33413453 | 18,876,037 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Keratitis bacterial'. | Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.
BACKGROUND
Burkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.
METHODS
We retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.
RESULTS
The most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.
CONCLUSIONS
B. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.
Background
Burkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.
Materials and methods
This single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.
Results
Table 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).
Table 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis
No. Age/
sex Year Risk factors Prior use
of cortico-
steroid Location
, size Hypopyon Corneal perforation Treatment Surgery Presenting
VA Final
VA Other isolates
1 71/f 2003 Diabetic mellitus − C, L + − Ceftazidime, Vancomycin − NLP NLP
2 52/m 2007 Ocular trauma + C, S + − Ceftazidime, Sulfamethoxazole/Trimethoprim AMT CF CF Candida parapsilosis
3 64/f 2010 Diabetic mellitus, Recent ocular surgery (PKP) + C, L − − Ceftazidime AMT, patch graft, evisceration NLP NLP
4 71/m 2010 HZV keratitis − C, L − + Amikacin, Vancomycin, Sulfamethoxazole/Trimethoprim − NLP NLP Serratia marcescens
5 24/m 2010 HSV keratitis + PC, L − − Ceftazidime, acyclovir − CF 20/200
6 57/f 2014 HSV keratitis − C, L − + Levofloxacin, acyclovir Patch graft, PKP HM LP
7 85/m 2016 Unknown − C, L + − Amikacin, voriconazole − HM HM Fusarium solani
8 53/m 2016 Ocular trauma + PC, M + + Ceftazidime, Moxifloxacin (oral), Vancomycin 20/200 20/70
9 84/f 2017 Ocular surface problem − PC, S − − Levofloxacin − CF CF
10 50/f 2017 Contact lens wear − PC, S − − Levofloxacin − 20/25 20/50
11 88/f 2017 Recent ocular surgery (PKP, AMT) + C, M + − Levofloxacin AMT HM 20/1000 Pseudomonas aeruginosa
12 60/m 2017 Unknown − C, L + − Levofloxacin AMT, keratectomy, tarsorrhaphy, patch graft CF NA
13 84/f 2018 HSV keratitis + PC, S + + Ceftazidime − HM CF
14 65/f 2018 Diabetic mellitus, Recurrent ocular ulcer + PC, M + − Levofloxacin − HM NLP Corynebacterium propinquum, Corynebacterium species
15 48/m 2018 Ocular trauma − PC, S − − Levofloxacin − 20/50 20/30 Bacillus megaterium,
Arthrobacter species
16 69/f 2019 Unknown − C, L − − Levofloxacin − NLP NLP Pseudomonas aeruginosa
17 36/m 2019 HZV keratitis, Contact lens wear + C, M − − Levofloxacin − CF 20/400
AMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity
Of the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.
Predisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.
Of the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.
All patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.
Visual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.
Case report (Patient 13)
An 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.
Fig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon
Discussion
B. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.
Table 2 Clinical data of the patients with Burkholderia capecia keratitis
Age/sex Risk factor Prior steroid use Location, size Hypopyon Medical treatment Surgery Presenting VA Final VA Other isolates\
Matoba et al. [7] 59/m HSV keratitis + C, M - Levofloxacin - CF 20/200 Enterococcus species, Staphylococcus aureus
Lin et al. [5] 16/f Ortho-keratology lens – PC, S – Ciprofloxacin – 20/40 20/20 Pseudomonas putida, Pseudomonas aeruginosa.
Ornek et al. [18]a 78/f Cataract surgery + C, M – Ciprofloxacin +IVI
Ceftazidime
– NLP NA
Chaurasia et al. [4] NA Unknown + NA, M – Ciprofloxacin Tissue adhesive LP NA
NA Unknown – NA, S + Ciprofloxacin – NA NA
NA Trauma – NA, L + Ciprofloxacin TPK LP NA
NA TPK + NA, S – Ceftazidime – HM NA
Reddy et al. [9] 27/m LASIK + C, multiple infiltrates + Tobramycin and Gatifloxacin CF 20/20
C central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty
a A case of keratitis and endophthalmitis
In our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.
In our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.
B. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).
The visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.
The retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.
In conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.
Abbreviation
VAVisual acuity
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
All authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.
Consent for publication
The consent for publication of biometric data from Patient 13 was obtained.
Competing interests
The authors declare that they have no competing interests. | ACYCLOVIR, PREDNISOLONE ACETATE | DrugsGivenReaction | CC BY | 33413453 | 18,876,037 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic response decreased'. | Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.
BACKGROUND
Burkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.
METHODS
We retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.
RESULTS
The most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.
CONCLUSIONS
B. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.
Background
Burkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.
Materials and methods
This single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.
Results
Table 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).
Table 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis
No. Age/
sex Year Risk factors Prior use
of cortico-
steroid Location
, size Hypopyon Corneal perforation Treatment Surgery Presenting
VA Final
VA Other isolates
1 71/f 2003 Diabetic mellitus − C, L + − Ceftazidime, Vancomycin − NLP NLP
2 52/m 2007 Ocular trauma + C, S + − Ceftazidime, Sulfamethoxazole/Trimethoprim AMT CF CF Candida parapsilosis
3 64/f 2010 Diabetic mellitus, Recent ocular surgery (PKP) + C, L − − Ceftazidime AMT, patch graft, evisceration NLP NLP
4 71/m 2010 HZV keratitis − C, L − + Amikacin, Vancomycin, Sulfamethoxazole/Trimethoprim − NLP NLP Serratia marcescens
5 24/m 2010 HSV keratitis + PC, L − − Ceftazidime, acyclovir − CF 20/200
6 57/f 2014 HSV keratitis − C, L − + Levofloxacin, acyclovir Patch graft, PKP HM LP
7 85/m 2016 Unknown − C, L + − Amikacin, voriconazole − HM HM Fusarium solani
8 53/m 2016 Ocular trauma + PC, M + + Ceftazidime, Moxifloxacin (oral), Vancomycin 20/200 20/70
9 84/f 2017 Ocular surface problem − PC, S − − Levofloxacin − CF CF
10 50/f 2017 Contact lens wear − PC, S − − Levofloxacin − 20/25 20/50
11 88/f 2017 Recent ocular surgery (PKP, AMT) + C, M + − Levofloxacin AMT HM 20/1000 Pseudomonas aeruginosa
12 60/m 2017 Unknown − C, L + − Levofloxacin AMT, keratectomy, tarsorrhaphy, patch graft CF NA
13 84/f 2018 HSV keratitis + PC, S + + Ceftazidime − HM CF
14 65/f 2018 Diabetic mellitus, Recurrent ocular ulcer + PC, M + − Levofloxacin − HM NLP Corynebacterium propinquum, Corynebacterium species
15 48/m 2018 Ocular trauma − PC, S − − Levofloxacin − 20/50 20/30 Bacillus megaterium,
Arthrobacter species
16 69/f 2019 Unknown − C, L − − Levofloxacin − NLP NLP Pseudomonas aeruginosa
17 36/m 2019 HZV keratitis, Contact lens wear + C, M − − Levofloxacin − CF 20/400
AMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity
Of the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.
Predisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.
Of the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.
All patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.
Visual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.
Case report (Patient 13)
An 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.
Fig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon
Discussion
B. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.
Table 2 Clinical data of the patients with Burkholderia capecia keratitis
Age/sex Risk factor Prior steroid use Location, size Hypopyon Medical treatment Surgery Presenting VA Final VA Other isolates\
Matoba et al. [7] 59/m HSV keratitis + C, M - Levofloxacin - CF 20/200 Enterococcus species, Staphylococcus aureus
Lin et al. [5] 16/f Ortho-keratology lens – PC, S – Ciprofloxacin – 20/40 20/20 Pseudomonas putida, Pseudomonas aeruginosa.
Ornek et al. [18]a 78/f Cataract surgery + C, M – Ciprofloxacin +IVI
Ceftazidime
– NLP NA
Chaurasia et al. [4] NA Unknown + NA, M – Ciprofloxacin Tissue adhesive LP NA
NA Unknown – NA, S + Ciprofloxacin – NA NA
NA Trauma – NA, L + Ciprofloxacin TPK LP NA
NA TPK + NA, S – Ceftazidime – HM NA
Reddy et al. [9] 27/m LASIK + C, multiple infiltrates + Tobramycin and Gatifloxacin CF 20/20
C central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty
a A case of keratitis and endophthalmitis
In our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.
In our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.
B. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).
The visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.
The retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.
In conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.
Abbreviation
VAVisual acuity
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
All authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.
Consent for publication
The consent for publication of biometric data from Patient 13 was obtained.
Competing interests
The authors declare that they have no competing interests. | CEFTAZIDIME, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY | 33413453 | 18,936,160 | 2021-01-07 |
What was the administration route of drug 'ACYCLOVIR'? | Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.
BACKGROUND
Burkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.
METHODS
We retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.
RESULTS
The most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.
CONCLUSIONS
B. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.
Background
Burkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.
Materials and methods
This single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.
Results
Table 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).
Table 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis
No. Age/
sex Year Risk factors Prior use
of cortico-
steroid Location
, size Hypopyon Corneal perforation Treatment Surgery Presenting
VA Final
VA Other isolates
1 71/f 2003 Diabetic mellitus − C, L + − Ceftazidime, Vancomycin − NLP NLP
2 52/m 2007 Ocular trauma + C, S + − Ceftazidime, Sulfamethoxazole/Trimethoprim AMT CF CF Candida parapsilosis
3 64/f 2010 Diabetic mellitus, Recent ocular surgery (PKP) + C, L − − Ceftazidime AMT, patch graft, evisceration NLP NLP
4 71/m 2010 HZV keratitis − C, L − + Amikacin, Vancomycin, Sulfamethoxazole/Trimethoprim − NLP NLP Serratia marcescens
5 24/m 2010 HSV keratitis + PC, L − − Ceftazidime, acyclovir − CF 20/200
6 57/f 2014 HSV keratitis − C, L − + Levofloxacin, acyclovir Patch graft, PKP HM LP
7 85/m 2016 Unknown − C, L + − Amikacin, voriconazole − HM HM Fusarium solani
8 53/m 2016 Ocular trauma + PC, M + + Ceftazidime, Moxifloxacin (oral), Vancomycin 20/200 20/70
9 84/f 2017 Ocular surface problem − PC, S − − Levofloxacin − CF CF
10 50/f 2017 Contact lens wear − PC, S − − Levofloxacin − 20/25 20/50
11 88/f 2017 Recent ocular surgery (PKP, AMT) + C, M + − Levofloxacin AMT HM 20/1000 Pseudomonas aeruginosa
12 60/m 2017 Unknown − C, L + − Levofloxacin AMT, keratectomy, tarsorrhaphy, patch graft CF NA
13 84/f 2018 HSV keratitis + PC, S + + Ceftazidime − HM CF
14 65/f 2018 Diabetic mellitus, Recurrent ocular ulcer + PC, M + − Levofloxacin − HM NLP Corynebacterium propinquum, Corynebacterium species
15 48/m 2018 Ocular trauma − PC, S − − Levofloxacin − 20/50 20/30 Bacillus megaterium,
Arthrobacter species
16 69/f 2019 Unknown − C, L − − Levofloxacin − NLP NLP Pseudomonas aeruginosa
17 36/m 2019 HZV keratitis, Contact lens wear + C, M − − Levofloxacin − CF 20/400
AMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity
Of the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.
Predisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.
Of the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.
All patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.
Visual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.
Case report (Patient 13)
An 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.
Fig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon
Discussion
B. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.
Table 2 Clinical data of the patients with Burkholderia capecia keratitis
Age/sex Risk factor Prior steroid use Location, size Hypopyon Medical treatment Surgery Presenting VA Final VA Other isolates\
Matoba et al. [7] 59/m HSV keratitis + C, M - Levofloxacin - CF 20/200 Enterococcus species, Staphylococcus aureus
Lin et al. [5] 16/f Ortho-keratology lens – PC, S – Ciprofloxacin – 20/40 20/20 Pseudomonas putida, Pseudomonas aeruginosa.
Ornek et al. [18]a 78/f Cataract surgery + C, M – Ciprofloxacin +IVI
Ceftazidime
– NLP NA
Chaurasia et al. [4] NA Unknown + NA, M – Ciprofloxacin Tissue adhesive LP NA
NA Unknown – NA, S + Ciprofloxacin – NA NA
NA Trauma – NA, L + Ciprofloxacin TPK LP NA
NA TPK + NA, S – Ceftazidime – HM NA
Reddy et al. [9] 27/m LASIK + C, multiple infiltrates + Tobramycin and Gatifloxacin CF 20/20
C central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty
a A case of keratitis and endophthalmitis
In our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.
In our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.
B. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).
The visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.
The retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.
In conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.
Abbreviation
VAVisual acuity
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
All authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.
Consent for publication
The consent for publication of biometric data from Patient 13 was obtained.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33413453 | 18,876,037 | 2021-01-07 |
What was the administration route of drug 'PREDNISOLONE ACETATE'? | Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.
BACKGROUND
Burkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.
METHODS
We retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.
RESULTS
The most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.
CONCLUSIONS
B. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.
Background
Burkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.
Materials and methods
This single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.
Results
Table 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).
Table 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis
No. Age/
sex Year Risk factors Prior use
of cortico-
steroid Location
, size Hypopyon Corneal perforation Treatment Surgery Presenting
VA Final
VA Other isolates
1 71/f 2003 Diabetic mellitus − C, L + − Ceftazidime, Vancomycin − NLP NLP
2 52/m 2007 Ocular trauma + C, S + − Ceftazidime, Sulfamethoxazole/Trimethoprim AMT CF CF Candida parapsilosis
3 64/f 2010 Diabetic mellitus, Recent ocular surgery (PKP) + C, L − − Ceftazidime AMT, patch graft, evisceration NLP NLP
4 71/m 2010 HZV keratitis − C, L − + Amikacin, Vancomycin, Sulfamethoxazole/Trimethoprim − NLP NLP Serratia marcescens
5 24/m 2010 HSV keratitis + PC, L − − Ceftazidime, acyclovir − CF 20/200
6 57/f 2014 HSV keratitis − C, L − + Levofloxacin, acyclovir Patch graft, PKP HM LP
7 85/m 2016 Unknown − C, L + − Amikacin, voriconazole − HM HM Fusarium solani
8 53/m 2016 Ocular trauma + PC, M + + Ceftazidime, Moxifloxacin (oral), Vancomycin 20/200 20/70
9 84/f 2017 Ocular surface problem − PC, S − − Levofloxacin − CF CF
10 50/f 2017 Contact lens wear − PC, S − − Levofloxacin − 20/25 20/50
11 88/f 2017 Recent ocular surgery (PKP, AMT) + C, M + − Levofloxacin AMT HM 20/1000 Pseudomonas aeruginosa
12 60/m 2017 Unknown − C, L + − Levofloxacin AMT, keratectomy, tarsorrhaphy, patch graft CF NA
13 84/f 2018 HSV keratitis + PC, S + + Ceftazidime − HM CF
14 65/f 2018 Diabetic mellitus, Recurrent ocular ulcer + PC, M + − Levofloxacin − HM NLP Corynebacterium propinquum, Corynebacterium species
15 48/m 2018 Ocular trauma − PC, S − − Levofloxacin − 20/50 20/30 Bacillus megaterium,
Arthrobacter species
16 69/f 2019 Unknown − C, L − − Levofloxacin − NLP NLP Pseudomonas aeruginosa
17 36/m 2019 HZV keratitis, Contact lens wear + C, M − − Levofloxacin − CF 20/400
AMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity
Of the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.
Predisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.
Of the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.
All patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.
Visual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.
Case report (Patient 13)
An 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.
Fig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon
Discussion
B. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.
Table 2 Clinical data of the patients with Burkholderia capecia keratitis
Age/sex Risk factor Prior steroid use Location, size Hypopyon Medical treatment Surgery Presenting VA Final VA Other isolates\
Matoba et al. [7] 59/m HSV keratitis + C, M - Levofloxacin - CF 20/200 Enterococcus species, Staphylococcus aureus
Lin et al. [5] 16/f Ortho-keratology lens – PC, S – Ciprofloxacin – 20/40 20/20 Pseudomonas putida, Pseudomonas aeruginosa.
Ornek et al. [18]a 78/f Cataract surgery + C, M – Ciprofloxacin +IVI
Ceftazidime
– NLP NA
Chaurasia et al. [4] NA Unknown + NA, M – Ciprofloxacin Tissue adhesive LP NA
NA Unknown – NA, S + Ciprofloxacin – NA NA
NA Trauma – NA, L + Ciprofloxacin TPK LP NA
NA TPK + NA, S – Ceftazidime – HM NA
Reddy et al. [9] 27/m LASIK + C, multiple infiltrates + Tobramycin and Gatifloxacin CF 20/20
C central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty
a A case of keratitis and endophthalmitis
In our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.
In our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.
B. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).
The visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.
The retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.
In conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.
Abbreviation
VAVisual acuity
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
All authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.
Consent for publication
The consent for publication of biometric data from Patient 13 was obtained.
Competing interests
The authors declare that they have no competing interests. | Topical | DrugAdministrationRoute | CC BY | 33413453 | 18,876,037 | 2021-01-07 |
What was the outcome of reaction 'Burkholderia cepacia complex infection'? | Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.
BACKGROUND
Burkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.
METHODS
We retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.
RESULTS
The most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.
CONCLUSIONS
B. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.
Background
Burkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.
Materials and methods
This single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.
Results
Table 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).
Table 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis
No. Age/
sex Year Risk factors Prior use
of cortico-
steroid Location
, size Hypopyon Corneal perforation Treatment Surgery Presenting
VA Final
VA Other isolates
1 71/f 2003 Diabetic mellitus − C, L + − Ceftazidime, Vancomycin − NLP NLP
2 52/m 2007 Ocular trauma + C, S + − Ceftazidime, Sulfamethoxazole/Trimethoprim AMT CF CF Candida parapsilosis
3 64/f 2010 Diabetic mellitus, Recent ocular surgery (PKP) + C, L − − Ceftazidime AMT, patch graft, evisceration NLP NLP
4 71/m 2010 HZV keratitis − C, L − + Amikacin, Vancomycin, Sulfamethoxazole/Trimethoprim − NLP NLP Serratia marcescens
5 24/m 2010 HSV keratitis + PC, L − − Ceftazidime, acyclovir − CF 20/200
6 57/f 2014 HSV keratitis − C, L − + Levofloxacin, acyclovir Patch graft, PKP HM LP
7 85/m 2016 Unknown − C, L + − Amikacin, voriconazole − HM HM Fusarium solani
8 53/m 2016 Ocular trauma + PC, M + + Ceftazidime, Moxifloxacin (oral), Vancomycin 20/200 20/70
9 84/f 2017 Ocular surface problem − PC, S − − Levofloxacin − CF CF
10 50/f 2017 Contact lens wear − PC, S − − Levofloxacin − 20/25 20/50
11 88/f 2017 Recent ocular surgery (PKP, AMT) + C, M + − Levofloxacin AMT HM 20/1000 Pseudomonas aeruginosa
12 60/m 2017 Unknown − C, L + − Levofloxacin AMT, keratectomy, tarsorrhaphy, patch graft CF NA
13 84/f 2018 HSV keratitis + PC, S + + Ceftazidime − HM CF
14 65/f 2018 Diabetic mellitus, Recurrent ocular ulcer + PC, M + − Levofloxacin − HM NLP Corynebacterium propinquum, Corynebacterium species
15 48/m 2018 Ocular trauma − PC, S − − Levofloxacin − 20/50 20/30 Bacillus megaterium,
Arthrobacter species
16 69/f 2019 Unknown − C, L − − Levofloxacin − NLP NLP Pseudomonas aeruginosa
17 36/m 2019 HZV keratitis, Contact lens wear + C, M − − Levofloxacin − CF 20/400
AMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity
Of the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.
Predisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.
Of the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.
All patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.
Visual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.
Case report (Patient 13)
An 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.
Fig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon
Discussion
B. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.
Table 2 Clinical data of the patients with Burkholderia capecia keratitis
Age/sex Risk factor Prior steroid use Location, size Hypopyon Medical treatment Surgery Presenting VA Final VA Other isolates\
Matoba et al. [7] 59/m HSV keratitis + C, M - Levofloxacin - CF 20/200 Enterococcus species, Staphylococcus aureus
Lin et al. [5] 16/f Ortho-keratology lens – PC, S – Ciprofloxacin – 20/40 20/20 Pseudomonas putida, Pseudomonas aeruginosa.
Ornek et al. [18]a 78/f Cataract surgery + C, M – Ciprofloxacin +IVI
Ceftazidime
– NLP NA
Chaurasia et al. [4] NA Unknown + NA, M – Ciprofloxacin Tissue adhesive LP NA
NA Unknown – NA, S + Ciprofloxacin – NA NA
NA Trauma – NA, L + Ciprofloxacin TPK LP NA
NA TPK + NA, S – Ceftazidime – HM NA
Reddy et al. [9] 27/m LASIK + C, multiple infiltrates + Tobramycin and Gatifloxacin CF 20/20
C central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty
a A case of keratitis and endophthalmitis
In our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.
In our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.
B. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).
The visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.
The retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.
In conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.
Abbreviation
VAVisual acuity
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
All authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.
Consent for publication
The consent for publication of biometric data from Patient 13 was obtained.
Competing interests
The authors declare that they have no competing interests. | Recovered with sequelae (consequent health issues) | ReactionOutcome | CC BY | 33413453 | 18,876,037 | 2021-01-07 |
What was the outcome of reaction 'Keratitis bacterial'? | Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.
BACKGROUND
Burkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.
METHODS
We retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.
RESULTS
The most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.
CONCLUSIONS
B. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.
Background
Burkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.
Materials and methods
This single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.
Results
Table 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).
Table 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis
No. Age/
sex Year Risk factors Prior use
of cortico-
steroid Location
, size Hypopyon Corneal perforation Treatment Surgery Presenting
VA Final
VA Other isolates
1 71/f 2003 Diabetic mellitus − C, L + − Ceftazidime, Vancomycin − NLP NLP
2 52/m 2007 Ocular trauma + C, S + − Ceftazidime, Sulfamethoxazole/Trimethoprim AMT CF CF Candida parapsilosis
3 64/f 2010 Diabetic mellitus, Recent ocular surgery (PKP) + C, L − − Ceftazidime AMT, patch graft, evisceration NLP NLP
4 71/m 2010 HZV keratitis − C, L − + Amikacin, Vancomycin, Sulfamethoxazole/Trimethoprim − NLP NLP Serratia marcescens
5 24/m 2010 HSV keratitis + PC, L − − Ceftazidime, acyclovir − CF 20/200
6 57/f 2014 HSV keratitis − C, L − + Levofloxacin, acyclovir Patch graft, PKP HM LP
7 85/m 2016 Unknown − C, L + − Amikacin, voriconazole − HM HM Fusarium solani
8 53/m 2016 Ocular trauma + PC, M + + Ceftazidime, Moxifloxacin (oral), Vancomycin 20/200 20/70
9 84/f 2017 Ocular surface problem − PC, S − − Levofloxacin − CF CF
10 50/f 2017 Contact lens wear − PC, S − − Levofloxacin − 20/25 20/50
11 88/f 2017 Recent ocular surgery (PKP, AMT) + C, M + − Levofloxacin AMT HM 20/1000 Pseudomonas aeruginosa
12 60/m 2017 Unknown − C, L + − Levofloxacin AMT, keratectomy, tarsorrhaphy, patch graft CF NA
13 84/f 2018 HSV keratitis + PC, S + + Ceftazidime − HM CF
14 65/f 2018 Diabetic mellitus, Recurrent ocular ulcer + PC, M + − Levofloxacin − HM NLP Corynebacterium propinquum, Corynebacterium species
15 48/m 2018 Ocular trauma − PC, S − − Levofloxacin − 20/50 20/30 Bacillus megaterium,
Arthrobacter species
16 69/f 2019 Unknown − C, L − − Levofloxacin − NLP NLP Pseudomonas aeruginosa
17 36/m 2019 HZV keratitis, Contact lens wear + C, M − − Levofloxacin − CF 20/400
AMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity
Of the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.
Predisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.
Of the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.
All patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.
Visual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.
Case report (Patient 13)
An 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.
Fig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon
Discussion
B. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.
Table 2 Clinical data of the patients with Burkholderia capecia keratitis
Age/sex Risk factor Prior steroid use Location, size Hypopyon Medical treatment Surgery Presenting VA Final VA Other isolates\
Matoba et al. [7] 59/m HSV keratitis + C, M - Levofloxacin - CF 20/200 Enterococcus species, Staphylococcus aureus
Lin et al. [5] 16/f Ortho-keratology lens – PC, S – Ciprofloxacin – 20/40 20/20 Pseudomonas putida, Pseudomonas aeruginosa.
Ornek et al. [18]a 78/f Cataract surgery + C, M – Ciprofloxacin +IVI
Ceftazidime
– NLP NA
Chaurasia et al. [4] NA Unknown + NA, M – Ciprofloxacin Tissue adhesive LP NA
NA Unknown – NA, S + Ciprofloxacin – NA NA
NA Trauma – NA, L + Ciprofloxacin TPK LP NA
NA TPK + NA, S – Ceftazidime – HM NA
Reddy et al. [9] 27/m LASIK + C, multiple infiltrates + Tobramycin and Gatifloxacin CF 20/20
C central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty
a A case of keratitis and endophthalmitis
In our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.
In our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.
B. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).
The visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.
The retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.
In conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.
Abbreviation
VAVisual acuity
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Authors’ contributions
All authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.
Ethics approval and consent to participate
The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.
Consent for publication
The consent for publication of biometric data from Patient 13 was obtained.
Competing interests
The authors declare that they have no competing interests. | Recovered with sequelae (consequent health issues) | ReactionOutcome | CC BY | 33413453 | 18,876,037 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | HUMAN IMMUNOGLOBULIN G, INFLIXIMAB, METHYLPREDNISOLONE, PREDNISONE | DrugsGivenReaction | CC BY-NC | 33414264 | 18,750,143 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia parainfluenzae viral'. | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | ALBUTEROL\IPRATROPIUM, AZTREONAM, CHLORHEXIDINE, ENOXAPARIN, FLUOXETINE HYDROCHLORIDE, INFLIXIMAB, INSULIN ASPART, LEVOTHYROXINE, METHYLPREDNISOLONE SODIUM SUCCINATE, MIDAZOLAM, MOXIFLOXACIN, PANTOPRAZOLE, PREDNISONE, PREGABALIN, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | HUMAN IMMUNOGLOBULIN G, INFLIXIMAB, METHYLPREDNISOLONE, PREDNISONE | DrugsGivenReaction | CC BY-NC | 33414264 | 18,750,143 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory tract infection'. | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | ALBUTEROL\IPRATROPIUM, AZTREONAM, CHLORHEXIDINE, ENOXAPARIN, FLUOXETINE HYDROCHLORIDE, INFLIXIMAB, INSULIN ASPART, LEVOTHYROXINE, METHYLPREDNISOLONE SODIUM SUCCINATE, MIDAZOLAM, MOXIFLOXACIN, PANTOPRAZOLE, PREDNISONE, PREGABALIN, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'AZTREONAM'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'ENOXAPARIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Subcutaneous | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'FLUOXETINE HYDROCHLORIDE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Oral | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,842,724 | 2021-01 |
What was the administration route of drug 'INFLIXIMAB'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'INSULIN ASPART'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Subcutaneous | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'LEVOTHYROXINE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'MOXIFLOXACIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'PANTOPRAZOLE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Oral | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'PREGABALIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Oral | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Oral | DrugAdministrationRoute | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the administration route of drug 'VANCOMYCIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
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What was the dosage of drug 'ALBUTEROL\IPRATROPIUM'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 3 ML (NEBULIZATION) Q6HR | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'AZTREONAM'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 2 G, Q8HR | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'CHLORHEXIDINE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 15 ML, Q12H (MOUTH/THROAT) | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'ENOXAPARIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 40 MG, BID | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'FLUOXETINE HYDROCHLORIDE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 40 MG, DAILY | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'INSULIN ASPART'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 0?6 UNITS, TID DURING MEALS | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'LEVOTHYROXINE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 38 MCG, DAILY | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
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What was the dosage of drug 'MIDAZOLAM'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 5 MG/HR | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'MOXIFLOXACIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 400 MG, Q24H | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'PANTOPRAZOLE'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 40 MG, DAILY | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'PREGABALIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 50 MG, BID | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 1 TABLET, ONCE PER DAY ON MON WED FRI | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the dosage of drug 'VANCOMYCIN'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | 15 MG/KG/DOSE, Q12H | DrugDosageText | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the outcome of reaction 'Condition aggravated'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Fatal | ReactionOutcome | CC BY-NC | 33414264 | 18,750,143 | 2021-01 |
What was the outcome of reaction 'Drug ineffective for unapproved indication'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Fatal | ReactionOutcome | CC BY-NC | 33414264 | 18,842,724 | 2021-01 |
What was the outcome of reaction 'Immune-mediated pneumonitis'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Fatal | ReactionOutcome | CC BY-NC | 33414264 | 18,842,724 | 2021-01 |
What was the outcome of reaction 'Off label use'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Fatal | ReactionOutcome | CC BY-NC | 33414264 | 18,842,724 | 2021-01 |
What was the outcome of reaction 'Pneumonia parainfluenzae viral'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Fatal | ReactionOutcome | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
What was the outcome of reaction 'Pneumonitis'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Fatal | ReactionOutcome | CC BY-NC | 33414264 | 18,750,143 | 2021-01 |
What was the outcome of reaction 'Respiratory tract infection'? | Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.
Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.
Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.
Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.
Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
pmcHighlights
Steroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.
Steroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.
Patients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.
Introduction
Immune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14
Published guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.
Given these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.
Methods
Study approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Patient selection
We retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.
Incidence
Incidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.
Steroid-refractory ICI-pneumonitis definition and diagnosis
The diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.
Radiology
Serial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2
Level-of-care
The level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28
Oxygen supplementation
The highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29
For patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31
Statistical analysis
Study data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.
Results
Incidence
The incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).
In the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.
Study population
Baseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.
10.1136/jitc-2020-001731.supp1 Supplementary data
Table 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Baseline characteristics
Age at ICI-pneumonitis diagnosis (mean, years) 66 66 68
Sex
Male 4 (57) 0 (0) 2 (67)
Female 3 (43) 2 (100) 1 (33)
Race
Caucasian 6 (86) 2 (100) 3 (100)
African-American 1 (14) 0 (0) 0 (0)
Smoking status
Never 3 (43) 0 (0) 0 (0)
Current/former 4 (57) 2 (100) 3 (100)
Pack year history (mean, years) 29.4 37.5 32.5
Tumor histology
Lung carcinoma 5 (71) 2 (100) 2 (67)
Non-small cell lung carcinoma 4 (80) 2 (100) 2 (100)
Small cell lung carcinoma 1 (20) 0 (0) 0 (0)
Oropharyngeal squamous cell carcinoma 0 (0) 0 (0) 1 (33)
Renal cell carcinoma 0 (0) 0 (0) 0 (0)
Pancreatic adenocarcinoma 0 (0) 0 (0) 0 (0)
Initial cancer stage*
II 1 (14) 1 (50) 1 (33)
III 3 (43) 0 (0) 0 (0)
IV 3 (43) 1 (50) 2 (67)
Anticancer therapy
Prior chemotherapy 6 (86) 2 (100) 3 (100)
Initial surgery 1 (14) 0 (0) 1 (33)
Prior chest radiation therapy† 4 (57) 1 (50) 2 (67)
PD-1/PD-L1 monotherapy 2 (29) 1 (50) 3 (100)
Durvalumab 2 (100) 0 (0) 1 (33)
Nivolumab 0 (0) 1 (100) 1 (33)
Pembrolizumab 0 (0) 0 (0) 1 (33)
PD-1/PD-L1-based combinations 5 (71) 1 (50) 0 (0)
Pembrolizumab+chemotherapy 4 (80) 0 (0) 0 (0)
Nivolumab+ipilimumab 1 (20) 1 (100) 0 (0)
ICI response at 3 months‡
Partial response 1 (14) 1 (50) 1 (33)
Stable disease 4 (57) 0 (0) 0 (0)
Progressive disease 2 (29) 1 (50) 2 (67)
*AJCC staging system.
†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.
‡As defined by RECIST V.1.1 criteria.
ICI, immune-checkpoint inhibitor; PD, progressive disease.
We identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.
Clinical features
The clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.
Table 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment
Therapy type Intravenous immunoglobulin Infliximab Combination
Total patients, n (%) 7 2 3
Steroid-refractory pneumonitis features
Initial CTCAE grade
2 3 (43) 0 (0) 0 (0)
3 4 (57) 2 (100) 3 (100)
ICI doses (mean, range) 5 (3–10) 7 (1–13) 2 (2–3)
ICI start to steroid-refractory pneumonitis onset, days (mean, range) 127 (39–208) 98 (14–182) 40 (21–77)
Hospital length of stay, days (mean, range) 21 (6–48) 13.5 (13–14) 20 (8–31)
Steroid-refractory pneumonitis management
Corticosteroid duration, days (mean, range) 59 (14–122) 58 (19–97) 26 (5–41)
First corticosteroid dose to first immunosuppression dose, days (mean, range) 17 (2–96) 8 (4–12) 2 (1–5)
Intubation for SRCIP 1 (14) 1 (50) 1 (33)
Diagnostic bronchoscopy with bronchoalveolar lavage 4 (57) 1 (50) 1 (33)
Pulmonology consult 7 (100) 2 (100) 3 (100)
Infectious disease consult 4 (57) 1 (50) 2 (67)
Steroid-refractory pneumonitis outcomes
CTCAE grade after immunosuppression
2 3 (43) 0 (0) 0 (0)
3 3 (43) 1 (50) 2 (67)
4 1 (14) 1 (50) 1 (33)
Infection after immunosuppression 1* (14) 1† (50) 0 (0)
Clinical outcome
Improved 2 (29) 0 (0) 0 (0)
Worsened 2 (29) 0 (0) 0 (0)
Death from steroid-refractory pneumonitis 3 (43) 2 (100) 3 (100)
*Herpes Zoster Shingles.
†Parainfluenza pneumonia.
CTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.
Patients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.
Steroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).
Radiographic features
We examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).
10.1136/jitc-2020-001731.supp2 Supplementary data
Figure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.
Immunosuppressive management and outcomes
Intravenous immunoglobulin
After lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).
Patient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.
Figure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.
Oxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).
Figure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.
In terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.
Infliximab
Two patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).
Both patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.
Neither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.
Both patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.
Combination immunosuppression
Three patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.
All three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.
In terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.
Taken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.
Discussion
In this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.
Steroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11
Importantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.
While our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).
In conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
Collection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.
Twitter: @AanikaBalaji, @DrJNaidoo
AB and MH contributed equally.
KS and JN contributed equally.
Correction notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.
Contributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Fatal | ReactionOutcome | CC BY-NC | 33414264 | 18,750,080 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Jejunal ulcer'. | Small intestinal thrombotic microangiopathy following kidney transplantation diagnosed by balloon-assisted enteroscopy.
Thrombotic microangiopathy (TMA) is a serious complication following kidney transplantation. Although intestinal TMA is a major organ injury and causes abdominal pain, diarrhea and bloody stools, the clinical and endoscopic characteristics of small intestinal TMA remain unclear. Here, we report a drug-induced small intestinal TMA, which did not meet the laboratory-defined TMA criteria but was diagnosed by balloon-assisted enteroscopy (BAE). A 32-year-old woman who underwent kidney transplantation at the age of 10 years complained of abdominal pain, diarrhea and bloody stools one month after starting everolimus (EVE) as an immunosuppressant. Although she did not meet the diagnostic criteria for TMA serologically, BAE revealed a circumferential ulcer in the jejunum, and the pathological findings of a biopsy specimen showed microvascular thrombi, compatible with intestinal TMA. Her symptoms improved upon the discontinuation of EVE, demonstrating that EVE can cause drug-induced intestinal TMA. The present case suggests that BAE should be performed when abdominal pain, diarrhea, and bloody stools occur in patients receiving immunosuppressive medication following kidney transplantation, even if there is no evidence of TMA according to the laboratory definition.
Introduction
Thrombotic microangiopathy (TMA) is a serious complication following renal transplantation and causes hemolytic anemia, thrombocytopenia and organ injury [1]. Intestinal TMA (iTMA) is one of the organ disorders caused by TMA and causes abdominal pain, diarrhea and bloody stools. When the laboratory criteria for TMA are not met, histological evaluation by endoscopic biopsy is necessary for the diagnosis of iTMA [2-4]. In recent years, various small intestinal diseases have been revealed by balloon-assisted enteroscopy (BAE), including double- and single-balloon enteroscopy. However, there are few reports of small intestinal TMA, and the clinical features and endoscopic findings remain unclear. Herein, we report a case of small intestinal TMA, following kidney transplantation, diagnosed by BAE.
Case report
A 32-year-old woman, who received a kidney transplant because of nephrotic syndrome at the age of 10 years, was admitted to our hospital with recurrent abdominal pain, diarrhea and bloody stools. Five months before admission, she was administered everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor, in addition to tacrolimus and methylprednisolone for rejection prophylaxis, and her symptoms developed 1 month after the start of EVE administration. She received antibacterial therapy, but her symptoms did not improve. On admission, initial laboratory findings revealed mild anemia, thrombocytopenia, and slightly elevated lactate dehydrogenase (LDH), while schistocytes were not observed (Table 1). Thus, laboratory findings did not show any evidence of TMA. Further, no evidence of an infection (i.e., cytomegalovirus or Epstein-Barr virus) was found. Plain computed tomography of the abdomen showed wall thickening of the small intestine and ascites; there was therefore no evidence of organ disorders other than of the digestive tract. Intestinal ultrasound examination showed wall thickening with increased blood flow in the small intestine (Fig. 1). In contrast, esophagogastroduodenoscopy (EGD) and colonoscopy results were within normal limits. Subsequently, double-balloon enteroscopy (DBE) was performed, which revealed a circumferential ulcer over 20 cm in length in the jejunum. Enteroclysis with gastrografin revealed a small intestinal stricture that coincided with the site of the ulcer (Fig. 2A,B). Histopathological findings of the small intestine biopsy specimen revealed shortened villi, hyperemia in the mucosa, and thrombi within small vessels in the submucosa, leading to the diagnosis of small intestinal TMA (Fig. 3). Considering the clinical course, with the symptoms of the patient appearing after EVE administration, she was diagnosed with EVE-induced TMA. Her symptoms, consisting of abdominal pain, diarrhea and bloody stools, improved after the discontinuation of EVE. Ulcer healing was observed by DBE 4 months after the discontinuation of EVE (Fig. 2C).
Table 1 Laboratory findings on admission
Figure 1 (A) Abdominal computed tomography shows wall thickening of the small intestine (yellow arrowheads) and ascites. No free air is found. (B) Abdominal ultrasound shows wall thickening with focally increased Doppler flow
Figure 2 (A) Endoscopic view of the small intestine on admission. A severe circumferential ulcer measuring over 20 cm in length was found in the jejunum. (B) Enteroclysis with gastrografin revealed a small intestinal stenosis at the ulcer site. Two stricture sites in the jejunum were skipped (yellow arrowheads). (C) Endoscopic view of the small intestine 4 months after the discontinuation of everolimus. The severe circumferential ulcer has healed without stricture
Figure 3 (A) Histopathological findings of the small intestinal biopsy specimen with hematoxylin and eosin staining revealed shortened villi and hyperemia in the mucosa. (B) Detail of the yellow box in (a); histopathological findings revealed thrombi within some small vessels in the submucosa, compatible with intestinal thrombotic microangiopathy
Discussion
Two key findings should be highlighted in this case. First, although the laboratory findings did not meet the TMA diagnostic criteria [5], a definitive diagnosis was achieved by performing DBE. In the criteria proposed by the European Group for Blood and Marrow Transplantation, TMA is defined as a syndrome with the following laboratory findings: i) hemolytic anemia; ii) thrombocytopenia; iii) a schistocyte count of >4%; iv) increased LDH; and v) decreased haptoglobin [5]. In the present case, thrombocytopenia was the only TMA criterion that was met. The clinical symptoms of iTMA are reported as abdominal pain, diarrhea and bloody stools, difficult to distinguish from graft-versus-host disease, an infection, and ischemic enteritis/colitis. On the other hand, previous studies have reported that some patients have been diagnosed with iTMA histologically, even if their laboratory findings do not meet the TMA criteria [2-4]. In such cases, histological investigation by endoscopic biopsy is important for the diagnosis of iTMA. To the best of our knowledge, the present report is the first iTMA case confined to the small intestine that could not be diagnosed by EGD and colonoscopy alone, but additionally required DBE. In recent years, BAE has become popular in many countries, but there have been no reports of small intestinal TMA diagnosed by BAE. The endoscopic findings of TMA in the duodenum and colon have been reported as edema, redness and ulcers [6,7], but since there have been only a limited number of reports, the endoscopic characteristics of iTMA have been unclear. The present case showed circumscribed and extensive ulcers, which were not found in the duodenum and colorectal lesions in previous reports. Given that cases of intestinal perforation due to iTMA have been reported, the early diagnosis of iTMA is important. However, since the risk of bleeding, perforation and aspiration pneumonia may be elevated in patients who are in poor general condition, the indication for BAE should be carefully considered. This case suggests that BAE is a useful tool for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain.
The second key finding to highlight is that EVE can cause intestinal TMA. mTOR inhibitors, including sirolimus and EVE, are known to cause TMA after kidney transplantation [1]. Previous studies have demonstrated that the risk of TMA is significantly increased in patients who receive a combination of mTOR inhibitors and calcineurin inhibitors, including tacrolimus and cyclosporine, compared to receiving either medication alone [8]. The initial treatment for drug-induced TMA is the discontinuation of the causative drug, and in the present case, iTMA was improved by the discontinuation of EVE. Eculizumab has been reported to be effective if improvement in TMA is not achieved by the discontinuation of the causative drug [9]. Although a previous study reported sirolimus-induced iTMA [10], there have been no reports of EVE-induced iTMA. Thus, to the best of our knowledge, the present case is also the first report of EVE-induced iTMA.
In conclusion, BAE is useful for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain. Furthermore, EVE may be the cause of small intestinal TMA. The present case suggests that BAE should be performed in patients taking immunosuppressive medication following kidney transplantation, who complain of abdominal pain, diarrhea and bloody stools, and yet have no abnormal EGD or colonoscopy findings, even if there is no evidence of TMA as defined by laboratory findings. Further accumulation of cases is needed to clarify the clinical course and endoscopic characteristics of small intestinal TMA.
Conflict of Interest: None
Yokohama City University Graduate School of Medicine, Yokohama, Japan | EVEROLIMUS, METHYLPREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC-SA | 33414631 | 18,901,717 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Small intestinal stenosis'. | Small intestinal thrombotic microangiopathy following kidney transplantation diagnosed by balloon-assisted enteroscopy.
Thrombotic microangiopathy (TMA) is a serious complication following kidney transplantation. Although intestinal TMA is a major organ injury and causes abdominal pain, diarrhea and bloody stools, the clinical and endoscopic characteristics of small intestinal TMA remain unclear. Here, we report a drug-induced small intestinal TMA, which did not meet the laboratory-defined TMA criteria but was diagnosed by balloon-assisted enteroscopy (BAE). A 32-year-old woman who underwent kidney transplantation at the age of 10 years complained of abdominal pain, diarrhea and bloody stools one month after starting everolimus (EVE) as an immunosuppressant. Although she did not meet the diagnostic criteria for TMA serologically, BAE revealed a circumferential ulcer in the jejunum, and the pathological findings of a biopsy specimen showed microvascular thrombi, compatible with intestinal TMA. Her symptoms improved upon the discontinuation of EVE, demonstrating that EVE can cause drug-induced intestinal TMA. The present case suggests that BAE should be performed when abdominal pain, diarrhea, and bloody stools occur in patients receiving immunosuppressive medication following kidney transplantation, even if there is no evidence of TMA according to the laboratory definition.
Introduction
Thrombotic microangiopathy (TMA) is a serious complication following renal transplantation and causes hemolytic anemia, thrombocytopenia and organ injury [1]. Intestinal TMA (iTMA) is one of the organ disorders caused by TMA and causes abdominal pain, diarrhea and bloody stools. When the laboratory criteria for TMA are not met, histological evaluation by endoscopic biopsy is necessary for the diagnosis of iTMA [2-4]. In recent years, various small intestinal diseases have been revealed by balloon-assisted enteroscopy (BAE), including double- and single-balloon enteroscopy. However, there are few reports of small intestinal TMA, and the clinical features and endoscopic findings remain unclear. Herein, we report a case of small intestinal TMA, following kidney transplantation, diagnosed by BAE.
Case report
A 32-year-old woman, who received a kidney transplant because of nephrotic syndrome at the age of 10 years, was admitted to our hospital with recurrent abdominal pain, diarrhea and bloody stools. Five months before admission, she was administered everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor, in addition to tacrolimus and methylprednisolone for rejection prophylaxis, and her symptoms developed 1 month after the start of EVE administration. She received antibacterial therapy, but her symptoms did not improve. On admission, initial laboratory findings revealed mild anemia, thrombocytopenia, and slightly elevated lactate dehydrogenase (LDH), while schistocytes were not observed (Table 1). Thus, laboratory findings did not show any evidence of TMA. Further, no evidence of an infection (i.e., cytomegalovirus or Epstein-Barr virus) was found. Plain computed tomography of the abdomen showed wall thickening of the small intestine and ascites; there was therefore no evidence of organ disorders other than of the digestive tract. Intestinal ultrasound examination showed wall thickening with increased blood flow in the small intestine (Fig. 1). In contrast, esophagogastroduodenoscopy (EGD) and colonoscopy results were within normal limits. Subsequently, double-balloon enteroscopy (DBE) was performed, which revealed a circumferential ulcer over 20 cm in length in the jejunum. Enteroclysis with gastrografin revealed a small intestinal stricture that coincided with the site of the ulcer (Fig. 2A,B). Histopathological findings of the small intestine biopsy specimen revealed shortened villi, hyperemia in the mucosa, and thrombi within small vessels in the submucosa, leading to the diagnosis of small intestinal TMA (Fig. 3). Considering the clinical course, with the symptoms of the patient appearing after EVE administration, she was diagnosed with EVE-induced TMA. Her symptoms, consisting of abdominal pain, diarrhea and bloody stools, improved after the discontinuation of EVE. Ulcer healing was observed by DBE 4 months after the discontinuation of EVE (Fig. 2C).
Table 1 Laboratory findings on admission
Figure 1 (A) Abdominal computed tomography shows wall thickening of the small intestine (yellow arrowheads) and ascites. No free air is found. (B) Abdominal ultrasound shows wall thickening with focally increased Doppler flow
Figure 2 (A) Endoscopic view of the small intestine on admission. A severe circumferential ulcer measuring over 20 cm in length was found in the jejunum. (B) Enteroclysis with gastrografin revealed a small intestinal stenosis at the ulcer site. Two stricture sites in the jejunum were skipped (yellow arrowheads). (C) Endoscopic view of the small intestine 4 months after the discontinuation of everolimus. The severe circumferential ulcer has healed without stricture
Figure 3 (A) Histopathological findings of the small intestinal biopsy specimen with hematoxylin and eosin staining revealed shortened villi and hyperemia in the mucosa. (B) Detail of the yellow box in (a); histopathological findings revealed thrombi within some small vessels in the submucosa, compatible with intestinal thrombotic microangiopathy
Discussion
Two key findings should be highlighted in this case. First, although the laboratory findings did not meet the TMA diagnostic criteria [5], a definitive diagnosis was achieved by performing DBE. In the criteria proposed by the European Group for Blood and Marrow Transplantation, TMA is defined as a syndrome with the following laboratory findings: i) hemolytic anemia; ii) thrombocytopenia; iii) a schistocyte count of >4%; iv) increased LDH; and v) decreased haptoglobin [5]. In the present case, thrombocytopenia was the only TMA criterion that was met. The clinical symptoms of iTMA are reported as abdominal pain, diarrhea and bloody stools, difficult to distinguish from graft-versus-host disease, an infection, and ischemic enteritis/colitis. On the other hand, previous studies have reported that some patients have been diagnosed with iTMA histologically, even if their laboratory findings do not meet the TMA criteria [2-4]. In such cases, histological investigation by endoscopic biopsy is important for the diagnosis of iTMA. To the best of our knowledge, the present report is the first iTMA case confined to the small intestine that could not be diagnosed by EGD and colonoscopy alone, but additionally required DBE. In recent years, BAE has become popular in many countries, but there have been no reports of small intestinal TMA diagnosed by BAE. The endoscopic findings of TMA in the duodenum and colon have been reported as edema, redness and ulcers [6,7], but since there have been only a limited number of reports, the endoscopic characteristics of iTMA have been unclear. The present case showed circumscribed and extensive ulcers, which were not found in the duodenum and colorectal lesions in previous reports. Given that cases of intestinal perforation due to iTMA have been reported, the early diagnosis of iTMA is important. However, since the risk of bleeding, perforation and aspiration pneumonia may be elevated in patients who are in poor general condition, the indication for BAE should be carefully considered. This case suggests that BAE is a useful tool for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain.
The second key finding to highlight is that EVE can cause intestinal TMA. mTOR inhibitors, including sirolimus and EVE, are known to cause TMA after kidney transplantation [1]. Previous studies have demonstrated that the risk of TMA is significantly increased in patients who receive a combination of mTOR inhibitors and calcineurin inhibitors, including tacrolimus and cyclosporine, compared to receiving either medication alone [8]. The initial treatment for drug-induced TMA is the discontinuation of the causative drug, and in the present case, iTMA was improved by the discontinuation of EVE. Eculizumab has been reported to be effective if improvement in TMA is not achieved by the discontinuation of the causative drug [9]. Although a previous study reported sirolimus-induced iTMA [10], there have been no reports of EVE-induced iTMA. Thus, to the best of our knowledge, the present case is also the first report of EVE-induced iTMA.
In conclusion, BAE is useful for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain. Furthermore, EVE may be the cause of small intestinal TMA. The present case suggests that BAE should be performed in patients taking immunosuppressive medication following kidney transplantation, who complain of abdominal pain, diarrhea and bloody stools, and yet have no abnormal EGD or colonoscopy findings, even if there is no evidence of TMA as defined by laboratory findings. Further accumulation of cases is needed to clarify the clinical course and endoscopic characteristics of small intestinal TMA.
Conflict of Interest: None
Yokohama City University Graduate School of Medicine, Yokohama, Japan | EVEROLIMUS, METHYLPREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC-SA | 33414631 | 18,901,717 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombotic microangiopathy'. | Small intestinal thrombotic microangiopathy following kidney transplantation diagnosed by balloon-assisted enteroscopy.
Thrombotic microangiopathy (TMA) is a serious complication following kidney transplantation. Although intestinal TMA is a major organ injury and causes abdominal pain, diarrhea and bloody stools, the clinical and endoscopic characteristics of small intestinal TMA remain unclear. Here, we report a drug-induced small intestinal TMA, which did not meet the laboratory-defined TMA criteria but was diagnosed by balloon-assisted enteroscopy (BAE). A 32-year-old woman who underwent kidney transplantation at the age of 10 years complained of abdominal pain, diarrhea and bloody stools one month after starting everolimus (EVE) as an immunosuppressant. Although she did not meet the diagnostic criteria for TMA serologically, BAE revealed a circumferential ulcer in the jejunum, and the pathological findings of a biopsy specimen showed microvascular thrombi, compatible with intestinal TMA. Her symptoms improved upon the discontinuation of EVE, demonstrating that EVE can cause drug-induced intestinal TMA. The present case suggests that BAE should be performed when abdominal pain, diarrhea, and bloody stools occur in patients receiving immunosuppressive medication following kidney transplantation, even if there is no evidence of TMA according to the laboratory definition.
Introduction
Thrombotic microangiopathy (TMA) is a serious complication following renal transplantation and causes hemolytic anemia, thrombocytopenia and organ injury [1]. Intestinal TMA (iTMA) is one of the organ disorders caused by TMA and causes abdominal pain, diarrhea and bloody stools. When the laboratory criteria for TMA are not met, histological evaluation by endoscopic biopsy is necessary for the diagnosis of iTMA [2-4]. In recent years, various small intestinal diseases have been revealed by balloon-assisted enteroscopy (BAE), including double- and single-balloon enteroscopy. However, there are few reports of small intestinal TMA, and the clinical features and endoscopic findings remain unclear. Herein, we report a case of small intestinal TMA, following kidney transplantation, diagnosed by BAE.
Case report
A 32-year-old woman, who received a kidney transplant because of nephrotic syndrome at the age of 10 years, was admitted to our hospital with recurrent abdominal pain, diarrhea and bloody stools. Five months before admission, she was administered everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor, in addition to tacrolimus and methylprednisolone for rejection prophylaxis, and her symptoms developed 1 month after the start of EVE administration. She received antibacterial therapy, but her symptoms did not improve. On admission, initial laboratory findings revealed mild anemia, thrombocytopenia, and slightly elevated lactate dehydrogenase (LDH), while schistocytes were not observed (Table 1). Thus, laboratory findings did not show any evidence of TMA. Further, no evidence of an infection (i.e., cytomegalovirus or Epstein-Barr virus) was found. Plain computed tomography of the abdomen showed wall thickening of the small intestine and ascites; there was therefore no evidence of organ disorders other than of the digestive tract. Intestinal ultrasound examination showed wall thickening with increased blood flow in the small intestine (Fig. 1). In contrast, esophagogastroduodenoscopy (EGD) and colonoscopy results were within normal limits. Subsequently, double-balloon enteroscopy (DBE) was performed, which revealed a circumferential ulcer over 20 cm in length in the jejunum. Enteroclysis with gastrografin revealed a small intestinal stricture that coincided with the site of the ulcer (Fig. 2A,B). Histopathological findings of the small intestine biopsy specimen revealed shortened villi, hyperemia in the mucosa, and thrombi within small vessels in the submucosa, leading to the diagnosis of small intestinal TMA (Fig. 3). Considering the clinical course, with the symptoms of the patient appearing after EVE administration, she was diagnosed with EVE-induced TMA. Her symptoms, consisting of abdominal pain, diarrhea and bloody stools, improved after the discontinuation of EVE. Ulcer healing was observed by DBE 4 months after the discontinuation of EVE (Fig. 2C).
Table 1 Laboratory findings on admission
Figure 1 (A) Abdominal computed tomography shows wall thickening of the small intestine (yellow arrowheads) and ascites. No free air is found. (B) Abdominal ultrasound shows wall thickening with focally increased Doppler flow
Figure 2 (A) Endoscopic view of the small intestine on admission. A severe circumferential ulcer measuring over 20 cm in length was found in the jejunum. (B) Enteroclysis with gastrografin revealed a small intestinal stenosis at the ulcer site. Two stricture sites in the jejunum were skipped (yellow arrowheads). (C) Endoscopic view of the small intestine 4 months after the discontinuation of everolimus. The severe circumferential ulcer has healed without stricture
Figure 3 (A) Histopathological findings of the small intestinal biopsy specimen with hematoxylin and eosin staining revealed shortened villi and hyperemia in the mucosa. (B) Detail of the yellow box in (a); histopathological findings revealed thrombi within some small vessels in the submucosa, compatible with intestinal thrombotic microangiopathy
Discussion
Two key findings should be highlighted in this case. First, although the laboratory findings did not meet the TMA diagnostic criteria [5], a definitive diagnosis was achieved by performing DBE. In the criteria proposed by the European Group for Blood and Marrow Transplantation, TMA is defined as a syndrome with the following laboratory findings: i) hemolytic anemia; ii) thrombocytopenia; iii) a schistocyte count of >4%; iv) increased LDH; and v) decreased haptoglobin [5]. In the present case, thrombocytopenia was the only TMA criterion that was met. The clinical symptoms of iTMA are reported as abdominal pain, diarrhea and bloody stools, difficult to distinguish from graft-versus-host disease, an infection, and ischemic enteritis/colitis. On the other hand, previous studies have reported that some patients have been diagnosed with iTMA histologically, even if their laboratory findings do not meet the TMA criteria [2-4]. In such cases, histological investigation by endoscopic biopsy is important for the diagnosis of iTMA. To the best of our knowledge, the present report is the first iTMA case confined to the small intestine that could not be diagnosed by EGD and colonoscopy alone, but additionally required DBE. In recent years, BAE has become popular in many countries, but there have been no reports of small intestinal TMA diagnosed by BAE. The endoscopic findings of TMA in the duodenum and colon have been reported as edema, redness and ulcers [6,7], but since there have been only a limited number of reports, the endoscopic characteristics of iTMA have been unclear. The present case showed circumscribed and extensive ulcers, which were not found in the duodenum and colorectal lesions in previous reports. Given that cases of intestinal perforation due to iTMA have been reported, the early diagnosis of iTMA is important. However, since the risk of bleeding, perforation and aspiration pneumonia may be elevated in patients who are in poor general condition, the indication for BAE should be carefully considered. This case suggests that BAE is a useful tool for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain.
The second key finding to highlight is that EVE can cause intestinal TMA. mTOR inhibitors, including sirolimus and EVE, are known to cause TMA after kidney transplantation [1]. Previous studies have demonstrated that the risk of TMA is significantly increased in patients who receive a combination of mTOR inhibitors and calcineurin inhibitors, including tacrolimus and cyclosporine, compared to receiving either medication alone [8]. The initial treatment for drug-induced TMA is the discontinuation of the causative drug, and in the present case, iTMA was improved by the discontinuation of EVE. Eculizumab has been reported to be effective if improvement in TMA is not achieved by the discontinuation of the causative drug [9]. Although a previous study reported sirolimus-induced iTMA [10], there have been no reports of EVE-induced iTMA. Thus, to the best of our knowledge, the present case is also the first report of EVE-induced iTMA.
In conclusion, BAE is useful for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain. Furthermore, EVE may be the cause of small intestinal TMA. The present case suggests that BAE should be performed in patients taking immunosuppressive medication following kidney transplantation, who complain of abdominal pain, diarrhea and bloody stools, and yet have no abnormal EGD or colonoscopy findings, even if there is no evidence of TMA as defined by laboratory findings. Further accumulation of cases is needed to clarify the clinical course and endoscopic characteristics of small intestinal TMA.
Conflict of Interest: None
Yokohama City University Graduate School of Medicine, Yokohama, Japan | EVEROLIMUS, METHYLPREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC-SA | 33414631 | 18,901,717 | 2021 |
What was the outcome of reaction 'Jejunal ulcer'? | Small intestinal thrombotic microangiopathy following kidney transplantation diagnosed by balloon-assisted enteroscopy.
Thrombotic microangiopathy (TMA) is a serious complication following kidney transplantation. Although intestinal TMA is a major organ injury and causes abdominal pain, diarrhea and bloody stools, the clinical and endoscopic characteristics of small intestinal TMA remain unclear. Here, we report a drug-induced small intestinal TMA, which did not meet the laboratory-defined TMA criteria but was diagnosed by balloon-assisted enteroscopy (BAE). A 32-year-old woman who underwent kidney transplantation at the age of 10 years complained of abdominal pain, diarrhea and bloody stools one month after starting everolimus (EVE) as an immunosuppressant. Although she did not meet the diagnostic criteria for TMA serologically, BAE revealed a circumferential ulcer in the jejunum, and the pathological findings of a biopsy specimen showed microvascular thrombi, compatible with intestinal TMA. Her symptoms improved upon the discontinuation of EVE, demonstrating that EVE can cause drug-induced intestinal TMA. The present case suggests that BAE should be performed when abdominal pain, diarrhea, and bloody stools occur in patients receiving immunosuppressive medication following kidney transplantation, even if there is no evidence of TMA according to the laboratory definition.
Introduction
Thrombotic microangiopathy (TMA) is a serious complication following renal transplantation and causes hemolytic anemia, thrombocytopenia and organ injury [1]. Intestinal TMA (iTMA) is one of the organ disorders caused by TMA and causes abdominal pain, diarrhea and bloody stools. When the laboratory criteria for TMA are not met, histological evaluation by endoscopic biopsy is necessary for the diagnosis of iTMA [2-4]. In recent years, various small intestinal diseases have been revealed by balloon-assisted enteroscopy (BAE), including double- and single-balloon enteroscopy. However, there are few reports of small intestinal TMA, and the clinical features and endoscopic findings remain unclear. Herein, we report a case of small intestinal TMA, following kidney transplantation, diagnosed by BAE.
Case report
A 32-year-old woman, who received a kidney transplant because of nephrotic syndrome at the age of 10 years, was admitted to our hospital with recurrent abdominal pain, diarrhea and bloody stools. Five months before admission, she was administered everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor, in addition to tacrolimus and methylprednisolone for rejection prophylaxis, and her symptoms developed 1 month after the start of EVE administration. She received antibacterial therapy, but her symptoms did not improve. On admission, initial laboratory findings revealed mild anemia, thrombocytopenia, and slightly elevated lactate dehydrogenase (LDH), while schistocytes were not observed (Table 1). Thus, laboratory findings did not show any evidence of TMA. Further, no evidence of an infection (i.e., cytomegalovirus or Epstein-Barr virus) was found. Plain computed tomography of the abdomen showed wall thickening of the small intestine and ascites; there was therefore no evidence of organ disorders other than of the digestive tract. Intestinal ultrasound examination showed wall thickening with increased blood flow in the small intestine (Fig. 1). In contrast, esophagogastroduodenoscopy (EGD) and colonoscopy results were within normal limits. Subsequently, double-balloon enteroscopy (DBE) was performed, which revealed a circumferential ulcer over 20 cm in length in the jejunum. Enteroclysis with gastrografin revealed a small intestinal stricture that coincided with the site of the ulcer (Fig. 2A,B). Histopathological findings of the small intestine biopsy specimen revealed shortened villi, hyperemia in the mucosa, and thrombi within small vessels in the submucosa, leading to the diagnosis of small intestinal TMA (Fig. 3). Considering the clinical course, with the symptoms of the patient appearing after EVE administration, she was diagnosed with EVE-induced TMA. Her symptoms, consisting of abdominal pain, diarrhea and bloody stools, improved after the discontinuation of EVE. Ulcer healing was observed by DBE 4 months after the discontinuation of EVE (Fig. 2C).
Table 1 Laboratory findings on admission
Figure 1 (A) Abdominal computed tomography shows wall thickening of the small intestine (yellow arrowheads) and ascites. No free air is found. (B) Abdominal ultrasound shows wall thickening with focally increased Doppler flow
Figure 2 (A) Endoscopic view of the small intestine on admission. A severe circumferential ulcer measuring over 20 cm in length was found in the jejunum. (B) Enteroclysis with gastrografin revealed a small intestinal stenosis at the ulcer site. Two stricture sites in the jejunum were skipped (yellow arrowheads). (C) Endoscopic view of the small intestine 4 months after the discontinuation of everolimus. The severe circumferential ulcer has healed without stricture
Figure 3 (A) Histopathological findings of the small intestinal biopsy specimen with hematoxylin and eosin staining revealed shortened villi and hyperemia in the mucosa. (B) Detail of the yellow box in (a); histopathological findings revealed thrombi within some small vessels in the submucosa, compatible with intestinal thrombotic microangiopathy
Discussion
Two key findings should be highlighted in this case. First, although the laboratory findings did not meet the TMA diagnostic criteria [5], a definitive diagnosis was achieved by performing DBE. In the criteria proposed by the European Group for Blood and Marrow Transplantation, TMA is defined as a syndrome with the following laboratory findings: i) hemolytic anemia; ii) thrombocytopenia; iii) a schistocyte count of >4%; iv) increased LDH; and v) decreased haptoglobin [5]. In the present case, thrombocytopenia was the only TMA criterion that was met. The clinical symptoms of iTMA are reported as abdominal pain, diarrhea and bloody stools, difficult to distinguish from graft-versus-host disease, an infection, and ischemic enteritis/colitis. On the other hand, previous studies have reported that some patients have been diagnosed with iTMA histologically, even if their laboratory findings do not meet the TMA criteria [2-4]. In such cases, histological investigation by endoscopic biopsy is important for the diagnosis of iTMA. To the best of our knowledge, the present report is the first iTMA case confined to the small intestine that could not be diagnosed by EGD and colonoscopy alone, but additionally required DBE. In recent years, BAE has become popular in many countries, but there have been no reports of small intestinal TMA diagnosed by BAE. The endoscopic findings of TMA in the duodenum and colon have been reported as edema, redness and ulcers [6,7], but since there have been only a limited number of reports, the endoscopic characteristics of iTMA have been unclear. The present case showed circumscribed and extensive ulcers, which were not found in the duodenum and colorectal lesions in previous reports. Given that cases of intestinal perforation due to iTMA have been reported, the early diagnosis of iTMA is important. However, since the risk of bleeding, perforation and aspiration pneumonia may be elevated in patients who are in poor general condition, the indication for BAE should be carefully considered. This case suggests that BAE is a useful tool for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain.
The second key finding to highlight is that EVE can cause intestinal TMA. mTOR inhibitors, including sirolimus and EVE, are known to cause TMA after kidney transplantation [1]. Previous studies have demonstrated that the risk of TMA is significantly increased in patients who receive a combination of mTOR inhibitors and calcineurin inhibitors, including tacrolimus and cyclosporine, compared to receiving either medication alone [8]. The initial treatment for drug-induced TMA is the discontinuation of the causative drug, and in the present case, iTMA was improved by the discontinuation of EVE. Eculizumab has been reported to be effective if improvement in TMA is not achieved by the discontinuation of the causative drug [9]. Although a previous study reported sirolimus-induced iTMA [10], there have been no reports of EVE-induced iTMA. Thus, to the best of our knowledge, the present case is also the first report of EVE-induced iTMA.
In conclusion, BAE is useful for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain. Furthermore, EVE may be the cause of small intestinal TMA. The present case suggests that BAE should be performed in patients taking immunosuppressive medication following kidney transplantation, who complain of abdominal pain, diarrhea and bloody stools, and yet have no abnormal EGD or colonoscopy findings, even if there is no evidence of TMA as defined by laboratory findings. Further accumulation of cases is needed to clarify the clinical course and endoscopic characteristics of small intestinal TMA.
Conflict of Interest: None
Yokohama City University Graduate School of Medicine, Yokohama, Japan | Recovering | ReactionOutcome | CC BY-NC-SA | 33414631 | 18,901,717 | 2021 |
What was the outcome of reaction 'Thrombotic microangiopathy'? | Small intestinal thrombotic microangiopathy following kidney transplantation diagnosed by balloon-assisted enteroscopy.
Thrombotic microangiopathy (TMA) is a serious complication following kidney transplantation. Although intestinal TMA is a major organ injury and causes abdominal pain, diarrhea and bloody stools, the clinical and endoscopic characteristics of small intestinal TMA remain unclear. Here, we report a drug-induced small intestinal TMA, which did not meet the laboratory-defined TMA criteria but was diagnosed by balloon-assisted enteroscopy (BAE). A 32-year-old woman who underwent kidney transplantation at the age of 10 years complained of abdominal pain, diarrhea and bloody stools one month after starting everolimus (EVE) as an immunosuppressant. Although she did not meet the diagnostic criteria for TMA serologically, BAE revealed a circumferential ulcer in the jejunum, and the pathological findings of a biopsy specimen showed microvascular thrombi, compatible with intestinal TMA. Her symptoms improved upon the discontinuation of EVE, demonstrating that EVE can cause drug-induced intestinal TMA. The present case suggests that BAE should be performed when abdominal pain, diarrhea, and bloody stools occur in patients receiving immunosuppressive medication following kidney transplantation, even if there is no evidence of TMA according to the laboratory definition.
Introduction
Thrombotic microangiopathy (TMA) is a serious complication following renal transplantation and causes hemolytic anemia, thrombocytopenia and organ injury [1]. Intestinal TMA (iTMA) is one of the organ disorders caused by TMA and causes abdominal pain, diarrhea and bloody stools. When the laboratory criteria for TMA are not met, histological evaluation by endoscopic biopsy is necessary for the diagnosis of iTMA [2-4]. In recent years, various small intestinal diseases have been revealed by balloon-assisted enteroscopy (BAE), including double- and single-balloon enteroscopy. However, there are few reports of small intestinal TMA, and the clinical features and endoscopic findings remain unclear. Herein, we report a case of small intestinal TMA, following kidney transplantation, diagnosed by BAE.
Case report
A 32-year-old woman, who received a kidney transplant because of nephrotic syndrome at the age of 10 years, was admitted to our hospital with recurrent abdominal pain, diarrhea and bloody stools. Five months before admission, she was administered everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor, in addition to tacrolimus and methylprednisolone for rejection prophylaxis, and her symptoms developed 1 month after the start of EVE administration. She received antibacterial therapy, but her symptoms did not improve. On admission, initial laboratory findings revealed mild anemia, thrombocytopenia, and slightly elevated lactate dehydrogenase (LDH), while schistocytes were not observed (Table 1). Thus, laboratory findings did not show any evidence of TMA. Further, no evidence of an infection (i.e., cytomegalovirus or Epstein-Barr virus) was found. Plain computed tomography of the abdomen showed wall thickening of the small intestine and ascites; there was therefore no evidence of organ disorders other than of the digestive tract. Intestinal ultrasound examination showed wall thickening with increased blood flow in the small intestine (Fig. 1). In contrast, esophagogastroduodenoscopy (EGD) and colonoscopy results were within normal limits. Subsequently, double-balloon enteroscopy (DBE) was performed, which revealed a circumferential ulcer over 20 cm in length in the jejunum. Enteroclysis with gastrografin revealed a small intestinal stricture that coincided with the site of the ulcer (Fig. 2A,B). Histopathological findings of the small intestine biopsy specimen revealed shortened villi, hyperemia in the mucosa, and thrombi within small vessels in the submucosa, leading to the diagnosis of small intestinal TMA (Fig. 3). Considering the clinical course, with the symptoms of the patient appearing after EVE administration, she was diagnosed with EVE-induced TMA. Her symptoms, consisting of abdominal pain, diarrhea and bloody stools, improved after the discontinuation of EVE. Ulcer healing was observed by DBE 4 months after the discontinuation of EVE (Fig. 2C).
Table 1 Laboratory findings on admission
Figure 1 (A) Abdominal computed tomography shows wall thickening of the small intestine (yellow arrowheads) and ascites. No free air is found. (B) Abdominal ultrasound shows wall thickening with focally increased Doppler flow
Figure 2 (A) Endoscopic view of the small intestine on admission. A severe circumferential ulcer measuring over 20 cm in length was found in the jejunum. (B) Enteroclysis with gastrografin revealed a small intestinal stenosis at the ulcer site. Two stricture sites in the jejunum were skipped (yellow arrowheads). (C) Endoscopic view of the small intestine 4 months after the discontinuation of everolimus. The severe circumferential ulcer has healed without stricture
Figure 3 (A) Histopathological findings of the small intestinal biopsy specimen with hematoxylin and eosin staining revealed shortened villi and hyperemia in the mucosa. (B) Detail of the yellow box in (a); histopathological findings revealed thrombi within some small vessels in the submucosa, compatible with intestinal thrombotic microangiopathy
Discussion
Two key findings should be highlighted in this case. First, although the laboratory findings did not meet the TMA diagnostic criteria [5], a definitive diagnosis was achieved by performing DBE. In the criteria proposed by the European Group for Blood and Marrow Transplantation, TMA is defined as a syndrome with the following laboratory findings: i) hemolytic anemia; ii) thrombocytopenia; iii) a schistocyte count of >4%; iv) increased LDH; and v) decreased haptoglobin [5]. In the present case, thrombocytopenia was the only TMA criterion that was met. The clinical symptoms of iTMA are reported as abdominal pain, diarrhea and bloody stools, difficult to distinguish from graft-versus-host disease, an infection, and ischemic enteritis/colitis. On the other hand, previous studies have reported that some patients have been diagnosed with iTMA histologically, even if their laboratory findings do not meet the TMA criteria [2-4]. In such cases, histological investigation by endoscopic biopsy is important for the diagnosis of iTMA. To the best of our knowledge, the present report is the first iTMA case confined to the small intestine that could not be diagnosed by EGD and colonoscopy alone, but additionally required DBE. In recent years, BAE has become popular in many countries, but there have been no reports of small intestinal TMA diagnosed by BAE. The endoscopic findings of TMA in the duodenum and colon have been reported as edema, redness and ulcers [6,7], but since there have been only a limited number of reports, the endoscopic characteristics of iTMA have been unclear. The present case showed circumscribed and extensive ulcers, which were not found in the duodenum and colorectal lesions in previous reports. Given that cases of intestinal perforation due to iTMA have been reported, the early diagnosis of iTMA is important. However, since the risk of bleeding, perforation and aspiration pneumonia may be elevated in patients who are in poor general condition, the indication for BAE should be carefully considered. This case suggests that BAE is a useful tool for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain.
The second key finding to highlight is that EVE can cause intestinal TMA. mTOR inhibitors, including sirolimus and EVE, are known to cause TMA after kidney transplantation [1]. Previous studies have demonstrated that the risk of TMA is significantly increased in patients who receive a combination of mTOR inhibitors and calcineurin inhibitors, including tacrolimus and cyclosporine, compared to receiving either medication alone [8]. The initial treatment for drug-induced TMA is the discontinuation of the causative drug, and in the present case, iTMA was improved by the discontinuation of EVE. Eculizumab has been reported to be effective if improvement in TMA is not achieved by the discontinuation of the causative drug [9]. Although a previous study reported sirolimus-induced iTMA [10], there have been no reports of EVE-induced iTMA. Thus, to the best of our knowledge, the present case is also the first report of EVE-induced iTMA.
In conclusion, BAE is useful for diagnosing TMA confined to the small intestine when a histopathological diagnosis is imperative, rather than a necessary procedure that should be performed in every post-transplant patient with bloody diarrhea and abdominal pain. Furthermore, EVE may be the cause of small intestinal TMA. The present case suggests that BAE should be performed in patients taking immunosuppressive medication following kidney transplantation, who complain of abdominal pain, diarrhea and bloody stools, and yet have no abnormal EGD or colonoscopy findings, even if there is no evidence of TMA as defined by laboratory findings. Further accumulation of cases is needed to clarify the clinical course and endoscopic characteristics of small intestinal TMA.
Conflict of Interest: None
Yokohama City University Graduate School of Medicine, Yokohama, Japan | Recovering | ReactionOutcome | CC BY-NC-SA | 33414631 | 18,901,717 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematemesis'. | Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
Introduction
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and TIE2], tumor microenvironment (platelet-derived growth factor receptor β (PDGFRβ) and fibroblast growth factor receptor-1), and oncogenesis (c-KIT, RET, RAF-1 and B-RAF) (1). Based on this mode of action, regorafenib has a broad spectrum of toxicities (2). To date, however, few reports have focused on autoimmune adverse events.
Case report
The patient was a Japanese woman who had a past medical history of chronic immune thrombocytopenic purpura (ITP) which developed at the age of 38 years and was treated with steroid therapy, which resulted in remission for more than 20 years without medication. She was diagnosed with recurrent colon cancer at age 66 years, after primary surgery and adjuvant chemotherapy with capecitabine plus oxaliplatin. She had received three lines of palliative chemotherapy including fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab, panitumumab monotherapy and trifluridine/tipiracil. Platelet-associated IgG (PAIgG) was not detected when FOLFIRI plus bevacizumab was initiated. High-grade thrombocytopenia was not observed during treatment for recurrent colon cancer.
As a standard therapy in the late-line setting for recurrent/metastatic colorectal cancer (3,4), treatment with regorafenib 160 mg orally once daily for 21 days on/7-days off in a 28-day cycle was initiated at the age of 68 years. Platelet count was 167x109/l on day 1 but dropped to 61x109/l on day 15, and regorafenib was continued. On day 18, she vomited blood and presented at the emergency department. Laboratory examination showed severe thrombocytopenia with a platelet count of 5x109/l (Table I). Petechiae and purpura in the extremities and hemorrhagic blisters in the oral mucosa were also observed (Fig. 1A). Multiple platelet transfusions were given, but the response was poor. Further laboratory examination showed increased PAIgG of 176 ng (normal range <27.6 ng) and negative IgG for H. pylori and heparin-induced thrombocytopenia antibody (Table I). There were no clinical manifestations suggested systemic lupus erythematosus (SLE), such as arthritis, mucocutaneous involvement or Raynaud's phenomenon. Diagnostic criteria of SLE were not met. Bone marrow examination revealed normal hematopoiesis, slightly increased megakaryocytes and no myelodysplasia or tumor metastasis (Fig. 1B). There was no evidence of other risk factors for exacerbation of ITP, including a history of taking any dietary supplements or medications, or viral infections. Taken together, these findings strongly suggested regorafenib exacerbated ITP. Regorafenib was permanently discontinued, and prednisone 1 mg/kg/day was administrated on day 21. The hemorrhagic diathesis resolved one week later, and the severe thrombocytopenia gradually recovered (Fig. 1C).
Discussion
Thrombocytopenia associated with regorafenib is not rare. A meta-analysis reported incidences of all-grade and high-grade thrombocytopenia 22 and 3%, respectively (5). Inhibition of VEGFR is a potential mechanism of regorafenib-induced myelosuppression (6,7). Conventional thrombocytopenia is associated with bone marrow hypoplasia and responds to blood transfusion. In the present case, in contrast, normal hematopoiesis was maintained, and thrombocytopenia was refractory to platelet transfusion, which is likely explained by an autoimmune mechanism.
Diagnosis of ITP requires exclusion of a variety of potential causes for thrombocytopenia. Many conditions which cause decreased platelet production such as bone marrow damage, infiltration and replacement of the bone marrow due to malignancies and myelodysplastic syndromes were excluded by findings form the bone marrow biopsy in the present case. Drug-induced thrombocytopenia (DITP) is difficult to be distinguished from ITP. However, a history of ITP and unrecovered thrombocytopenia after discontinuation of regorafenib suggested more likely ITP than DITP (8). Moreover, a very low platelet count nadir less than 20x109/l, response to steroid and a positive anti-platelet autoantibody test are supposed to help precise diagnosis of ITP from expert opinions (9,10). Based on the above, the diagnosis of ITP was very likely.
ITP is an autoimmune disease which is characterized by platelet destruction associated with antibodies to platelets and megakaryocyte dysfunction (11). The pathogenesis of ITP is complicated and has not been fully clarified. Recent findings suggest that dysfunction of mesenchymal stem cells (MSCs) plays an important role (12,13). MSCs derived from ITP patients (MSCs-ITP) showed impaired self-proliferative capacity and the loss of immunosuppressive function. Interestingly, treatment of MSCs-ITP with PDGF-BB, a ligand of PDGFRβ, could reverse the defect of MSC-ITP in vitro (13). In this basis, regorafenib-induced inhibition of PDGF-BB/PDGFRβ signaling might trigger dysfunction of MSCs, resulting in the exacerbation of ITP. VEGF/VEGFR signaling is another important target of regorafenib, however, exacerbation of ITP had not occurred during bevacizumab containing treatment in the first-line setting at age of 66 years, which supports the hypothesis above.
Several multi-kinase inhibitors other than regorafenib also inhibit PDGF/PDGFR signaling, which may exacerbate ITP. Imatinib and sunitinib have been reported to induce immune thrombocytopenia (14,15), albeit that these studies did not investigate the possibility of pre-existing MSC dysfunction.
In conclusion, we report the first case of regorafenib-induced exacerbation of ITP in remission. This case report highlights the need for caution with regard to regorafenib treatment in cancer patients with concomitant ITP.
Acknowledgements
The authors would like to thank Dr Maki Kanzawa (Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan) for pathological diagnosis.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, KY, AH and NK made substantial contributions to the acquisition of the data. SK, YI and KY drafted the manuscript. AH, TK, YFuj, YFun, MT, NK, HMa and HMi made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Clinical and pathological findings. (A) Petechiae and purpura in the extremities on day 21. (B) Histopathologic findings of bone marrow examination. Trilineage hematopoiesis was maintained. The megakaryocyte count was slightly increased. Myelodysplasia or tumor metastasis were not observed. Scale bar, 100 µm. (C) Clinical course of treatment with regorafenib and immune thrombocytopenic purpura. Green arrows indicate 10 units of platelet transfusion. Prednisone (1 mg/kg/day) was administered from day 21 and reduced to 0.8 mg/kg/day on day 45. As the platelet count decreased, prednisone was again increased to 1 mg/kg/day on day 59.
Table I Laboratory data.
Variable Reference range Result
White blood cell count, 100/µl 33-86 50
Red blood cell count, 106/µl 3.86-4.92 2.90
Hemoglobin, g/dl 11.6-14.8 9.3
Hematocrit, % 35.1-44.4 28.4
Platelet count, 109/l 158-348 5
Immature platelet fraction, % 1-4.8 16.3
APTT, sec 25.0-38.0 31.6
PT, % 70.0-130.0 94.0
Fibrinogen, mg/dl 200-400 298
D dimer, µg/ml <1 4.1
Lactate dehydrogenase, U/l 124-222 615
Aspartate transaminase, U/l 13-30 32
Alanine aminotransferase, U/l 7-23 17
Total bilirubin, mg/ml 0.4-1.5 1.6
Creatinine, mg/dl 0.46-0.79 0.87
Blood urea nitrogen, mg/dl 8-20 26.8
C-reactive protein, mg/dl 0.00-0.14 1.55
PA IgG, ng/107 cells <27.6 176.8
50% complement hemolysis, U/ml 25-51 30.2
Complement C3, mg/dl 73-138 72
Complement C4, mg/dl 11-31 11
Antinuclear antibody, IF <40 320x
Antinuclear antibody pattern Centromere pattern
HIT antibody, U/ml <1 <0.6
IgG antibody for H. pylori, U/ml <10 3
Hepatitis B surface antigen, IU/ml <0.0049 <0.003
Hepatitis C virus antibodies, COI <0.99 0.04
HIV antibody/antigen combo assay, S/CO <0.99 0.12
APTT, activated partial thromboplastin time; COI, cutoff index; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; IF, indirect immunofluorescence; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PA IgG, platelet-associated IgG; PT, prothrombin time; S/CO, signal-to-cutoff. | REGORAFENIB | DrugsGivenReaction | CC BY-NC-ND | 33414911 | 18,800,829 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune thrombocytopenia'. | Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
Introduction
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and TIE2], tumor microenvironment (platelet-derived growth factor receptor β (PDGFRβ) and fibroblast growth factor receptor-1), and oncogenesis (c-KIT, RET, RAF-1 and B-RAF) (1). Based on this mode of action, regorafenib has a broad spectrum of toxicities (2). To date, however, few reports have focused on autoimmune adverse events.
Case report
The patient was a Japanese woman who had a past medical history of chronic immune thrombocytopenic purpura (ITP) which developed at the age of 38 years and was treated with steroid therapy, which resulted in remission for more than 20 years without medication. She was diagnosed with recurrent colon cancer at age 66 years, after primary surgery and adjuvant chemotherapy with capecitabine plus oxaliplatin. She had received three lines of palliative chemotherapy including fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab, panitumumab monotherapy and trifluridine/tipiracil. Platelet-associated IgG (PAIgG) was not detected when FOLFIRI plus bevacizumab was initiated. High-grade thrombocytopenia was not observed during treatment for recurrent colon cancer.
As a standard therapy in the late-line setting for recurrent/metastatic colorectal cancer (3,4), treatment with regorafenib 160 mg orally once daily for 21 days on/7-days off in a 28-day cycle was initiated at the age of 68 years. Platelet count was 167x109/l on day 1 but dropped to 61x109/l on day 15, and regorafenib was continued. On day 18, she vomited blood and presented at the emergency department. Laboratory examination showed severe thrombocytopenia with a platelet count of 5x109/l (Table I). Petechiae and purpura in the extremities and hemorrhagic blisters in the oral mucosa were also observed (Fig. 1A). Multiple platelet transfusions were given, but the response was poor. Further laboratory examination showed increased PAIgG of 176 ng (normal range <27.6 ng) and negative IgG for H. pylori and heparin-induced thrombocytopenia antibody (Table I). There were no clinical manifestations suggested systemic lupus erythematosus (SLE), such as arthritis, mucocutaneous involvement or Raynaud's phenomenon. Diagnostic criteria of SLE were not met. Bone marrow examination revealed normal hematopoiesis, slightly increased megakaryocytes and no myelodysplasia or tumor metastasis (Fig. 1B). There was no evidence of other risk factors for exacerbation of ITP, including a history of taking any dietary supplements or medications, or viral infections. Taken together, these findings strongly suggested regorafenib exacerbated ITP. Regorafenib was permanently discontinued, and prednisone 1 mg/kg/day was administrated on day 21. The hemorrhagic diathesis resolved one week later, and the severe thrombocytopenia gradually recovered (Fig. 1C).
Discussion
Thrombocytopenia associated with regorafenib is not rare. A meta-analysis reported incidences of all-grade and high-grade thrombocytopenia 22 and 3%, respectively (5). Inhibition of VEGFR is a potential mechanism of regorafenib-induced myelosuppression (6,7). Conventional thrombocytopenia is associated with bone marrow hypoplasia and responds to blood transfusion. In the present case, in contrast, normal hematopoiesis was maintained, and thrombocytopenia was refractory to platelet transfusion, which is likely explained by an autoimmune mechanism.
Diagnosis of ITP requires exclusion of a variety of potential causes for thrombocytopenia. Many conditions which cause decreased platelet production such as bone marrow damage, infiltration and replacement of the bone marrow due to malignancies and myelodysplastic syndromes were excluded by findings form the bone marrow biopsy in the present case. Drug-induced thrombocytopenia (DITP) is difficult to be distinguished from ITP. However, a history of ITP and unrecovered thrombocytopenia after discontinuation of regorafenib suggested more likely ITP than DITP (8). Moreover, a very low platelet count nadir less than 20x109/l, response to steroid and a positive anti-platelet autoantibody test are supposed to help precise diagnosis of ITP from expert opinions (9,10). Based on the above, the diagnosis of ITP was very likely.
ITP is an autoimmune disease which is characterized by platelet destruction associated with antibodies to platelets and megakaryocyte dysfunction (11). The pathogenesis of ITP is complicated and has not been fully clarified. Recent findings suggest that dysfunction of mesenchymal stem cells (MSCs) plays an important role (12,13). MSCs derived from ITP patients (MSCs-ITP) showed impaired self-proliferative capacity and the loss of immunosuppressive function. Interestingly, treatment of MSCs-ITP with PDGF-BB, a ligand of PDGFRβ, could reverse the defect of MSC-ITP in vitro (13). In this basis, regorafenib-induced inhibition of PDGF-BB/PDGFRβ signaling might trigger dysfunction of MSCs, resulting in the exacerbation of ITP. VEGF/VEGFR signaling is another important target of regorafenib, however, exacerbation of ITP had not occurred during bevacizumab containing treatment in the first-line setting at age of 66 years, which supports the hypothesis above.
Several multi-kinase inhibitors other than regorafenib also inhibit PDGF/PDGFR signaling, which may exacerbate ITP. Imatinib and sunitinib have been reported to induce immune thrombocytopenia (14,15), albeit that these studies did not investigate the possibility of pre-existing MSC dysfunction.
In conclusion, we report the first case of regorafenib-induced exacerbation of ITP in remission. This case report highlights the need for caution with regard to regorafenib treatment in cancer patients with concomitant ITP.
Acknowledgements
The authors would like to thank Dr Maki Kanzawa (Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan) for pathological diagnosis.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, KY, AH and NK made substantial contributions to the acquisition of the data. SK, YI and KY drafted the manuscript. AH, TK, YFuj, YFun, MT, NK, HMa and HMi made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Clinical and pathological findings. (A) Petechiae and purpura in the extremities on day 21. (B) Histopathologic findings of bone marrow examination. Trilineage hematopoiesis was maintained. The megakaryocyte count was slightly increased. Myelodysplasia or tumor metastasis were not observed. Scale bar, 100 µm. (C) Clinical course of treatment with regorafenib and immune thrombocytopenic purpura. Green arrows indicate 10 units of platelet transfusion. Prednisone (1 mg/kg/day) was administered from day 21 and reduced to 0.8 mg/kg/day on day 45. As the platelet count decreased, prednisone was again increased to 1 mg/kg/day on day 59.
Table I Laboratory data.
Variable Reference range Result
White blood cell count, 100/µl 33-86 50
Red blood cell count, 106/µl 3.86-4.92 2.90
Hemoglobin, g/dl 11.6-14.8 9.3
Hematocrit, % 35.1-44.4 28.4
Platelet count, 109/l 158-348 5
Immature platelet fraction, % 1-4.8 16.3
APTT, sec 25.0-38.0 31.6
PT, % 70.0-130.0 94.0
Fibrinogen, mg/dl 200-400 298
D dimer, µg/ml <1 4.1
Lactate dehydrogenase, U/l 124-222 615
Aspartate transaminase, U/l 13-30 32
Alanine aminotransferase, U/l 7-23 17
Total bilirubin, mg/ml 0.4-1.5 1.6
Creatinine, mg/dl 0.46-0.79 0.87
Blood urea nitrogen, mg/dl 8-20 26.8
C-reactive protein, mg/dl 0.00-0.14 1.55
PA IgG, ng/107 cells <27.6 176.8
50% complement hemolysis, U/ml 25-51 30.2
Complement C3, mg/dl 73-138 72
Complement C4, mg/dl 11-31 11
Antinuclear antibody, IF <40 320x
Antinuclear antibody pattern Centromere pattern
HIT antibody, U/ml <1 <0.6
IgG antibody for H. pylori, U/ml <10 3
Hepatitis B surface antigen, IU/ml <0.0049 <0.003
Hepatitis C virus antibodies, COI <0.99 0.04
HIV antibody/antigen combo assay, S/CO <0.99 0.12
APTT, activated partial thromboplastin time; COI, cutoff index; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; IF, indirect immunofluorescence; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PA IgG, platelet-associated IgG; PT, prothrombin time; S/CO, signal-to-cutoff. | REGORAFENIB | DrugsGivenReaction | CC BY-NC-ND | 33414911 | 18,800,829 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
Introduction
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and TIE2], tumor microenvironment (platelet-derived growth factor receptor β (PDGFRβ) and fibroblast growth factor receptor-1), and oncogenesis (c-KIT, RET, RAF-1 and B-RAF) (1). Based on this mode of action, regorafenib has a broad spectrum of toxicities (2). To date, however, few reports have focused on autoimmune adverse events.
Case report
The patient was a Japanese woman who had a past medical history of chronic immune thrombocytopenic purpura (ITP) which developed at the age of 38 years and was treated with steroid therapy, which resulted in remission for more than 20 years without medication. She was diagnosed with recurrent colon cancer at age 66 years, after primary surgery and adjuvant chemotherapy with capecitabine plus oxaliplatin. She had received three lines of palliative chemotherapy including fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab, panitumumab monotherapy and trifluridine/tipiracil. Platelet-associated IgG (PAIgG) was not detected when FOLFIRI plus bevacizumab was initiated. High-grade thrombocytopenia was not observed during treatment for recurrent colon cancer.
As a standard therapy in the late-line setting for recurrent/metastatic colorectal cancer (3,4), treatment with regorafenib 160 mg orally once daily for 21 days on/7-days off in a 28-day cycle was initiated at the age of 68 years. Platelet count was 167x109/l on day 1 but dropped to 61x109/l on day 15, and regorafenib was continued. On day 18, she vomited blood and presented at the emergency department. Laboratory examination showed severe thrombocytopenia with a platelet count of 5x109/l (Table I). Petechiae and purpura in the extremities and hemorrhagic blisters in the oral mucosa were also observed (Fig. 1A). Multiple platelet transfusions were given, but the response was poor. Further laboratory examination showed increased PAIgG of 176 ng (normal range <27.6 ng) and negative IgG for H. pylori and heparin-induced thrombocytopenia antibody (Table I). There were no clinical manifestations suggested systemic lupus erythematosus (SLE), such as arthritis, mucocutaneous involvement or Raynaud's phenomenon. Diagnostic criteria of SLE were not met. Bone marrow examination revealed normal hematopoiesis, slightly increased megakaryocytes and no myelodysplasia or tumor metastasis (Fig. 1B). There was no evidence of other risk factors for exacerbation of ITP, including a history of taking any dietary supplements or medications, or viral infections. Taken together, these findings strongly suggested regorafenib exacerbated ITP. Regorafenib was permanently discontinued, and prednisone 1 mg/kg/day was administrated on day 21. The hemorrhagic diathesis resolved one week later, and the severe thrombocytopenia gradually recovered (Fig. 1C).
Discussion
Thrombocytopenia associated with regorafenib is not rare. A meta-analysis reported incidences of all-grade and high-grade thrombocytopenia 22 and 3%, respectively (5). Inhibition of VEGFR is a potential mechanism of regorafenib-induced myelosuppression (6,7). Conventional thrombocytopenia is associated with bone marrow hypoplasia and responds to blood transfusion. In the present case, in contrast, normal hematopoiesis was maintained, and thrombocytopenia was refractory to platelet transfusion, which is likely explained by an autoimmune mechanism.
Diagnosis of ITP requires exclusion of a variety of potential causes for thrombocytopenia. Many conditions which cause decreased platelet production such as bone marrow damage, infiltration and replacement of the bone marrow due to malignancies and myelodysplastic syndromes were excluded by findings form the bone marrow biopsy in the present case. Drug-induced thrombocytopenia (DITP) is difficult to be distinguished from ITP. However, a history of ITP and unrecovered thrombocytopenia after discontinuation of regorafenib suggested more likely ITP than DITP (8). Moreover, a very low platelet count nadir less than 20x109/l, response to steroid and a positive anti-platelet autoantibody test are supposed to help precise diagnosis of ITP from expert opinions (9,10). Based on the above, the diagnosis of ITP was very likely.
ITP is an autoimmune disease which is characterized by platelet destruction associated with antibodies to platelets and megakaryocyte dysfunction (11). The pathogenesis of ITP is complicated and has not been fully clarified. Recent findings suggest that dysfunction of mesenchymal stem cells (MSCs) plays an important role (12,13). MSCs derived from ITP patients (MSCs-ITP) showed impaired self-proliferative capacity and the loss of immunosuppressive function. Interestingly, treatment of MSCs-ITP with PDGF-BB, a ligand of PDGFRβ, could reverse the defect of MSC-ITP in vitro (13). In this basis, regorafenib-induced inhibition of PDGF-BB/PDGFRβ signaling might trigger dysfunction of MSCs, resulting in the exacerbation of ITP. VEGF/VEGFR signaling is another important target of regorafenib, however, exacerbation of ITP had not occurred during bevacizumab containing treatment in the first-line setting at age of 66 years, which supports the hypothesis above.
Several multi-kinase inhibitors other than regorafenib also inhibit PDGF/PDGFR signaling, which may exacerbate ITP. Imatinib and sunitinib have been reported to induce immune thrombocytopenia (14,15), albeit that these studies did not investigate the possibility of pre-existing MSC dysfunction.
In conclusion, we report the first case of regorafenib-induced exacerbation of ITP in remission. This case report highlights the need for caution with regard to regorafenib treatment in cancer patients with concomitant ITP.
Acknowledgements
The authors would like to thank Dr Maki Kanzawa (Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan) for pathological diagnosis.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, KY, AH and NK made substantial contributions to the acquisition of the data. SK, YI and KY drafted the manuscript. AH, TK, YFuj, YFun, MT, NK, HMa and HMi made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Clinical and pathological findings. (A) Petechiae and purpura in the extremities on day 21. (B) Histopathologic findings of bone marrow examination. Trilineage hematopoiesis was maintained. The megakaryocyte count was slightly increased. Myelodysplasia or tumor metastasis were not observed. Scale bar, 100 µm. (C) Clinical course of treatment with regorafenib and immune thrombocytopenic purpura. Green arrows indicate 10 units of platelet transfusion. Prednisone (1 mg/kg/day) was administered from day 21 and reduced to 0.8 mg/kg/day on day 45. As the platelet count decreased, prednisone was again increased to 1 mg/kg/day on day 59.
Table I Laboratory data.
Variable Reference range Result
White blood cell count, 100/µl 33-86 50
Red blood cell count, 106/µl 3.86-4.92 2.90
Hemoglobin, g/dl 11.6-14.8 9.3
Hematocrit, % 35.1-44.4 28.4
Platelet count, 109/l 158-348 5
Immature platelet fraction, % 1-4.8 16.3
APTT, sec 25.0-38.0 31.6
PT, % 70.0-130.0 94.0
Fibrinogen, mg/dl 200-400 298
D dimer, µg/ml <1 4.1
Lactate dehydrogenase, U/l 124-222 615
Aspartate transaminase, U/l 13-30 32
Alanine aminotransferase, U/l 7-23 17
Total bilirubin, mg/ml 0.4-1.5 1.6
Creatinine, mg/dl 0.46-0.79 0.87
Blood urea nitrogen, mg/dl 8-20 26.8
C-reactive protein, mg/dl 0.00-0.14 1.55
PA IgG, ng/107 cells <27.6 176.8
50% complement hemolysis, U/ml 25-51 30.2
Complement C3, mg/dl 73-138 72
Complement C4, mg/dl 11-31 11
Antinuclear antibody, IF <40 320x
Antinuclear antibody pattern Centromere pattern
HIT antibody, U/ml <1 <0.6
IgG antibody for H. pylori, U/ml <10 3
Hepatitis B surface antigen, IU/ml <0.0049 <0.003
Hepatitis C virus antibodies, COI <0.99 0.04
HIV antibody/antigen combo assay, S/CO <0.99 0.12
APTT, activated partial thromboplastin time; COI, cutoff index; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; IF, indirect immunofluorescence; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PA IgG, platelet-associated IgG; PT, prothrombin time; S/CO, signal-to-cutoff. | REGORAFENIB | DrugsGivenReaction | CC BY-NC-ND | 33414911 | 18,800,829 | 2021-02 |
What was the administration route of drug 'REGORAFENIB'? | Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
Introduction
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and TIE2], tumor microenvironment (platelet-derived growth factor receptor β (PDGFRβ) and fibroblast growth factor receptor-1), and oncogenesis (c-KIT, RET, RAF-1 and B-RAF) (1). Based on this mode of action, regorafenib has a broad spectrum of toxicities (2). To date, however, few reports have focused on autoimmune adverse events.
Case report
The patient was a Japanese woman who had a past medical history of chronic immune thrombocytopenic purpura (ITP) which developed at the age of 38 years and was treated with steroid therapy, which resulted in remission for more than 20 years without medication. She was diagnosed with recurrent colon cancer at age 66 years, after primary surgery and adjuvant chemotherapy with capecitabine plus oxaliplatin. She had received three lines of palliative chemotherapy including fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab, panitumumab monotherapy and trifluridine/tipiracil. Platelet-associated IgG (PAIgG) was not detected when FOLFIRI plus bevacizumab was initiated. High-grade thrombocytopenia was not observed during treatment for recurrent colon cancer.
As a standard therapy in the late-line setting for recurrent/metastatic colorectal cancer (3,4), treatment with regorafenib 160 mg orally once daily for 21 days on/7-days off in a 28-day cycle was initiated at the age of 68 years. Platelet count was 167x109/l on day 1 but dropped to 61x109/l on day 15, and regorafenib was continued. On day 18, she vomited blood and presented at the emergency department. Laboratory examination showed severe thrombocytopenia with a platelet count of 5x109/l (Table I). Petechiae and purpura in the extremities and hemorrhagic blisters in the oral mucosa were also observed (Fig. 1A). Multiple platelet transfusions were given, but the response was poor. Further laboratory examination showed increased PAIgG of 176 ng (normal range <27.6 ng) and negative IgG for H. pylori and heparin-induced thrombocytopenia antibody (Table I). There were no clinical manifestations suggested systemic lupus erythematosus (SLE), such as arthritis, mucocutaneous involvement or Raynaud's phenomenon. Diagnostic criteria of SLE were not met. Bone marrow examination revealed normal hematopoiesis, slightly increased megakaryocytes and no myelodysplasia or tumor metastasis (Fig. 1B). There was no evidence of other risk factors for exacerbation of ITP, including a history of taking any dietary supplements or medications, or viral infections. Taken together, these findings strongly suggested regorafenib exacerbated ITP. Regorafenib was permanently discontinued, and prednisone 1 mg/kg/day was administrated on day 21. The hemorrhagic diathesis resolved one week later, and the severe thrombocytopenia gradually recovered (Fig. 1C).
Discussion
Thrombocytopenia associated with regorafenib is not rare. A meta-analysis reported incidences of all-grade and high-grade thrombocytopenia 22 and 3%, respectively (5). Inhibition of VEGFR is a potential mechanism of regorafenib-induced myelosuppression (6,7). Conventional thrombocytopenia is associated with bone marrow hypoplasia and responds to blood transfusion. In the present case, in contrast, normal hematopoiesis was maintained, and thrombocytopenia was refractory to platelet transfusion, which is likely explained by an autoimmune mechanism.
Diagnosis of ITP requires exclusion of a variety of potential causes for thrombocytopenia. Many conditions which cause decreased platelet production such as bone marrow damage, infiltration and replacement of the bone marrow due to malignancies and myelodysplastic syndromes were excluded by findings form the bone marrow biopsy in the present case. Drug-induced thrombocytopenia (DITP) is difficult to be distinguished from ITP. However, a history of ITP and unrecovered thrombocytopenia after discontinuation of regorafenib suggested more likely ITP than DITP (8). Moreover, a very low platelet count nadir less than 20x109/l, response to steroid and a positive anti-platelet autoantibody test are supposed to help precise diagnosis of ITP from expert opinions (9,10). Based on the above, the diagnosis of ITP was very likely.
ITP is an autoimmune disease which is characterized by platelet destruction associated with antibodies to platelets and megakaryocyte dysfunction (11). The pathogenesis of ITP is complicated and has not been fully clarified. Recent findings suggest that dysfunction of mesenchymal stem cells (MSCs) plays an important role (12,13). MSCs derived from ITP patients (MSCs-ITP) showed impaired self-proliferative capacity and the loss of immunosuppressive function. Interestingly, treatment of MSCs-ITP with PDGF-BB, a ligand of PDGFRβ, could reverse the defect of MSC-ITP in vitro (13). In this basis, regorafenib-induced inhibition of PDGF-BB/PDGFRβ signaling might trigger dysfunction of MSCs, resulting in the exacerbation of ITP. VEGF/VEGFR signaling is another important target of regorafenib, however, exacerbation of ITP had not occurred during bevacizumab containing treatment in the first-line setting at age of 66 years, which supports the hypothesis above.
Several multi-kinase inhibitors other than regorafenib also inhibit PDGF/PDGFR signaling, which may exacerbate ITP. Imatinib and sunitinib have been reported to induce immune thrombocytopenia (14,15), albeit that these studies did not investigate the possibility of pre-existing MSC dysfunction.
In conclusion, we report the first case of regorafenib-induced exacerbation of ITP in remission. This case report highlights the need for caution with regard to regorafenib treatment in cancer patients with concomitant ITP.
Acknowledgements
The authors would like to thank Dr Maki Kanzawa (Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan) for pathological diagnosis.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, KY, AH and NK made substantial contributions to the acquisition of the data. SK, YI and KY drafted the manuscript. AH, TK, YFuj, YFun, MT, NK, HMa and HMi made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Clinical and pathological findings. (A) Petechiae and purpura in the extremities on day 21. (B) Histopathologic findings of bone marrow examination. Trilineage hematopoiesis was maintained. The megakaryocyte count was slightly increased. Myelodysplasia or tumor metastasis were not observed. Scale bar, 100 µm. (C) Clinical course of treatment with regorafenib and immune thrombocytopenic purpura. Green arrows indicate 10 units of platelet transfusion. Prednisone (1 mg/kg/day) was administered from day 21 and reduced to 0.8 mg/kg/day on day 45. As the platelet count decreased, prednisone was again increased to 1 mg/kg/day on day 59.
Table I Laboratory data.
Variable Reference range Result
White blood cell count, 100/µl 33-86 50
Red blood cell count, 106/µl 3.86-4.92 2.90
Hemoglobin, g/dl 11.6-14.8 9.3
Hematocrit, % 35.1-44.4 28.4
Platelet count, 109/l 158-348 5
Immature platelet fraction, % 1-4.8 16.3
APTT, sec 25.0-38.0 31.6
PT, % 70.0-130.0 94.0
Fibrinogen, mg/dl 200-400 298
D dimer, µg/ml <1 4.1
Lactate dehydrogenase, U/l 124-222 615
Aspartate transaminase, U/l 13-30 32
Alanine aminotransferase, U/l 7-23 17
Total bilirubin, mg/ml 0.4-1.5 1.6
Creatinine, mg/dl 0.46-0.79 0.87
Blood urea nitrogen, mg/dl 8-20 26.8
C-reactive protein, mg/dl 0.00-0.14 1.55
PA IgG, ng/107 cells <27.6 176.8
50% complement hemolysis, U/ml 25-51 30.2
Complement C3, mg/dl 73-138 72
Complement C4, mg/dl 11-31 11
Antinuclear antibody, IF <40 320x
Antinuclear antibody pattern Centromere pattern
HIT antibody, U/ml <1 <0.6
IgG antibody for H. pylori, U/ml <10 3
Hepatitis B surface antigen, IU/ml <0.0049 <0.003
Hepatitis C virus antibodies, COI <0.99 0.04
HIV antibody/antigen combo assay, S/CO <0.99 0.12
APTT, activated partial thromboplastin time; COI, cutoff index; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; IF, indirect immunofluorescence; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PA IgG, platelet-associated IgG; PT, prothrombin time; S/CO, signal-to-cutoff. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33414911 | 18,800,829 | 2021-02 |
What was the outcome of reaction 'Haematemesis'? | Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
Introduction
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and TIE2], tumor microenvironment (platelet-derived growth factor receptor β (PDGFRβ) and fibroblast growth factor receptor-1), and oncogenesis (c-KIT, RET, RAF-1 and B-RAF) (1). Based on this mode of action, regorafenib has a broad spectrum of toxicities (2). To date, however, few reports have focused on autoimmune adverse events.
Case report
The patient was a Japanese woman who had a past medical history of chronic immune thrombocytopenic purpura (ITP) which developed at the age of 38 years and was treated with steroid therapy, which resulted in remission for more than 20 years without medication. She was diagnosed with recurrent colon cancer at age 66 years, after primary surgery and adjuvant chemotherapy with capecitabine plus oxaliplatin. She had received three lines of palliative chemotherapy including fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab, panitumumab monotherapy and trifluridine/tipiracil. Platelet-associated IgG (PAIgG) was not detected when FOLFIRI plus bevacizumab was initiated. High-grade thrombocytopenia was not observed during treatment for recurrent colon cancer.
As a standard therapy in the late-line setting for recurrent/metastatic colorectal cancer (3,4), treatment with regorafenib 160 mg orally once daily for 21 days on/7-days off in a 28-day cycle was initiated at the age of 68 years. Platelet count was 167x109/l on day 1 but dropped to 61x109/l on day 15, and regorafenib was continued. On day 18, she vomited blood and presented at the emergency department. Laboratory examination showed severe thrombocytopenia with a platelet count of 5x109/l (Table I). Petechiae and purpura in the extremities and hemorrhagic blisters in the oral mucosa were also observed (Fig. 1A). Multiple platelet transfusions were given, but the response was poor. Further laboratory examination showed increased PAIgG of 176 ng (normal range <27.6 ng) and negative IgG for H. pylori and heparin-induced thrombocytopenia antibody (Table I). There were no clinical manifestations suggested systemic lupus erythematosus (SLE), such as arthritis, mucocutaneous involvement or Raynaud's phenomenon. Diagnostic criteria of SLE were not met. Bone marrow examination revealed normal hematopoiesis, slightly increased megakaryocytes and no myelodysplasia or tumor metastasis (Fig. 1B). There was no evidence of other risk factors for exacerbation of ITP, including a history of taking any dietary supplements or medications, or viral infections. Taken together, these findings strongly suggested regorafenib exacerbated ITP. Regorafenib was permanently discontinued, and prednisone 1 mg/kg/day was administrated on day 21. The hemorrhagic diathesis resolved one week later, and the severe thrombocytopenia gradually recovered (Fig. 1C).
Discussion
Thrombocytopenia associated with regorafenib is not rare. A meta-analysis reported incidences of all-grade and high-grade thrombocytopenia 22 and 3%, respectively (5). Inhibition of VEGFR is a potential mechanism of regorafenib-induced myelosuppression (6,7). Conventional thrombocytopenia is associated with bone marrow hypoplasia and responds to blood transfusion. In the present case, in contrast, normal hematopoiesis was maintained, and thrombocytopenia was refractory to platelet transfusion, which is likely explained by an autoimmune mechanism.
Diagnosis of ITP requires exclusion of a variety of potential causes for thrombocytopenia. Many conditions which cause decreased platelet production such as bone marrow damage, infiltration and replacement of the bone marrow due to malignancies and myelodysplastic syndromes were excluded by findings form the bone marrow biopsy in the present case. Drug-induced thrombocytopenia (DITP) is difficult to be distinguished from ITP. However, a history of ITP and unrecovered thrombocytopenia after discontinuation of regorafenib suggested more likely ITP than DITP (8). Moreover, a very low platelet count nadir less than 20x109/l, response to steroid and a positive anti-platelet autoantibody test are supposed to help precise diagnosis of ITP from expert opinions (9,10). Based on the above, the diagnosis of ITP was very likely.
ITP is an autoimmune disease which is characterized by platelet destruction associated with antibodies to platelets and megakaryocyte dysfunction (11). The pathogenesis of ITP is complicated and has not been fully clarified. Recent findings suggest that dysfunction of mesenchymal stem cells (MSCs) plays an important role (12,13). MSCs derived from ITP patients (MSCs-ITP) showed impaired self-proliferative capacity and the loss of immunosuppressive function. Interestingly, treatment of MSCs-ITP with PDGF-BB, a ligand of PDGFRβ, could reverse the defect of MSC-ITP in vitro (13). In this basis, regorafenib-induced inhibition of PDGF-BB/PDGFRβ signaling might trigger dysfunction of MSCs, resulting in the exacerbation of ITP. VEGF/VEGFR signaling is another important target of regorafenib, however, exacerbation of ITP had not occurred during bevacizumab containing treatment in the first-line setting at age of 66 years, which supports the hypothesis above.
Several multi-kinase inhibitors other than regorafenib also inhibit PDGF/PDGFR signaling, which may exacerbate ITP. Imatinib and sunitinib have been reported to induce immune thrombocytopenia (14,15), albeit that these studies did not investigate the possibility of pre-existing MSC dysfunction.
In conclusion, we report the first case of regorafenib-induced exacerbation of ITP in remission. This case report highlights the need for caution with regard to regorafenib treatment in cancer patients with concomitant ITP.
Acknowledgements
The authors would like to thank Dr Maki Kanzawa (Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan) for pathological diagnosis.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, KY, AH and NK made substantial contributions to the acquisition of the data. SK, YI and KY drafted the manuscript. AH, TK, YFuj, YFun, MT, NK, HMa and HMi made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Clinical and pathological findings. (A) Petechiae and purpura in the extremities on day 21. (B) Histopathologic findings of bone marrow examination. Trilineage hematopoiesis was maintained. The megakaryocyte count was slightly increased. Myelodysplasia or tumor metastasis were not observed. Scale bar, 100 µm. (C) Clinical course of treatment with regorafenib and immune thrombocytopenic purpura. Green arrows indicate 10 units of platelet transfusion. Prednisone (1 mg/kg/day) was administered from day 21 and reduced to 0.8 mg/kg/day on day 45. As the platelet count decreased, prednisone was again increased to 1 mg/kg/day on day 59.
Table I Laboratory data.
Variable Reference range Result
White blood cell count, 100/µl 33-86 50
Red blood cell count, 106/µl 3.86-4.92 2.90
Hemoglobin, g/dl 11.6-14.8 9.3
Hematocrit, % 35.1-44.4 28.4
Platelet count, 109/l 158-348 5
Immature platelet fraction, % 1-4.8 16.3
APTT, sec 25.0-38.0 31.6
PT, % 70.0-130.0 94.0
Fibrinogen, mg/dl 200-400 298
D dimer, µg/ml <1 4.1
Lactate dehydrogenase, U/l 124-222 615
Aspartate transaminase, U/l 13-30 32
Alanine aminotransferase, U/l 7-23 17
Total bilirubin, mg/ml 0.4-1.5 1.6
Creatinine, mg/dl 0.46-0.79 0.87
Blood urea nitrogen, mg/dl 8-20 26.8
C-reactive protein, mg/dl 0.00-0.14 1.55
PA IgG, ng/107 cells <27.6 176.8
50% complement hemolysis, U/ml 25-51 30.2
Complement C3, mg/dl 73-138 72
Complement C4, mg/dl 11-31 11
Antinuclear antibody, IF <40 320x
Antinuclear antibody pattern Centromere pattern
HIT antibody, U/ml <1 <0.6
IgG antibody for H. pylori, U/ml <10 3
Hepatitis B surface antigen, IU/ml <0.0049 <0.003
Hepatitis C virus antibodies, COI <0.99 0.04
HIV antibody/antigen combo assay, S/CO <0.99 0.12
APTT, activated partial thromboplastin time; COI, cutoff index; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; IF, indirect immunofluorescence; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PA IgG, platelet-associated IgG; PT, prothrombin time; S/CO, signal-to-cutoff. | Recovered | ReactionOutcome | CC BY-NC-ND | 33414911 | 18,800,829 | 2021-02 |
What was the outcome of reaction 'Immune thrombocytopenia'? | Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
Introduction
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and TIE2], tumor microenvironment (platelet-derived growth factor receptor β (PDGFRβ) and fibroblast growth factor receptor-1), and oncogenesis (c-KIT, RET, RAF-1 and B-RAF) (1). Based on this mode of action, regorafenib has a broad spectrum of toxicities (2). To date, however, few reports have focused on autoimmune adverse events.
Case report
The patient was a Japanese woman who had a past medical history of chronic immune thrombocytopenic purpura (ITP) which developed at the age of 38 years and was treated with steroid therapy, which resulted in remission for more than 20 years without medication. She was diagnosed with recurrent colon cancer at age 66 years, after primary surgery and adjuvant chemotherapy with capecitabine plus oxaliplatin. She had received three lines of palliative chemotherapy including fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab, panitumumab monotherapy and trifluridine/tipiracil. Platelet-associated IgG (PAIgG) was not detected when FOLFIRI plus bevacizumab was initiated. High-grade thrombocytopenia was not observed during treatment for recurrent colon cancer.
As a standard therapy in the late-line setting for recurrent/metastatic colorectal cancer (3,4), treatment with regorafenib 160 mg orally once daily for 21 days on/7-days off in a 28-day cycle was initiated at the age of 68 years. Platelet count was 167x109/l on day 1 but dropped to 61x109/l on day 15, and regorafenib was continued. On day 18, she vomited blood and presented at the emergency department. Laboratory examination showed severe thrombocytopenia with a platelet count of 5x109/l (Table I). Petechiae and purpura in the extremities and hemorrhagic blisters in the oral mucosa were also observed (Fig. 1A). Multiple platelet transfusions were given, but the response was poor. Further laboratory examination showed increased PAIgG of 176 ng (normal range <27.6 ng) and negative IgG for H. pylori and heparin-induced thrombocytopenia antibody (Table I). There were no clinical manifestations suggested systemic lupus erythematosus (SLE), such as arthritis, mucocutaneous involvement or Raynaud's phenomenon. Diagnostic criteria of SLE were not met. Bone marrow examination revealed normal hematopoiesis, slightly increased megakaryocytes and no myelodysplasia or tumor metastasis (Fig. 1B). There was no evidence of other risk factors for exacerbation of ITP, including a history of taking any dietary supplements or medications, or viral infections. Taken together, these findings strongly suggested regorafenib exacerbated ITP. Regorafenib was permanently discontinued, and prednisone 1 mg/kg/day was administrated on day 21. The hemorrhagic diathesis resolved one week later, and the severe thrombocytopenia gradually recovered (Fig. 1C).
Discussion
Thrombocytopenia associated with regorafenib is not rare. A meta-analysis reported incidences of all-grade and high-grade thrombocytopenia 22 and 3%, respectively (5). Inhibition of VEGFR is a potential mechanism of regorafenib-induced myelosuppression (6,7). Conventional thrombocytopenia is associated with bone marrow hypoplasia and responds to blood transfusion. In the present case, in contrast, normal hematopoiesis was maintained, and thrombocytopenia was refractory to platelet transfusion, which is likely explained by an autoimmune mechanism.
Diagnosis of ITP requires exclusion of a variety of potential causes for thrombocytopenia. Many conditions which cause decreased platelet production such as bone marrow damage, infiltration and replacement of the bone marrow due to malignancies and myelodysplastic syndromes were excluded by findings form the bone marrow biopsy in the present case. Drug-induced thrombocytopenia (DITP) is difficult to be distinguished from ITP. However, a history of ITP and unrecovered thrombocytopenia after discontinuation of regorafenib suggested more likely ITP than DITP (8). Moreover, a very low platelet count nadir less than 20x109/l, response to steroid and a positive anti-platelet autoantibody test are supposed to help precise diagnosis of ITP from expert opinions (9,10). Based on the above, the diagnosis of ITP was very likely.
ITP is an autoimmune disease which is characterized by platelet destruction associated with antibodies to platelets and megakaryocyte dysfunction (11). The pathogenesis of ITP is complicated and has not been fully clarified. Recent findings suggest that dysfunction of mesenchymal stem cells (MSCs) plays an important role (12,13). MSCs derived from ITP patients (MSCs-ITP) showed impaired self-proliferative capacity and the loss of immunosuppressive function. Interestingly, treatment of MSCs-ITP with PDGF-BB, a ligand of PDGFRβ, could reverse the defect of MSC-ITP in vitro (13). In this basis, regorafenib-induced inhibition of PDGF-BB/PDGFRβ signaling might trigger dysfunction of MSCs, resulting in the exacerbation of ITP. VEGF/VEGFR signaling is another important target of regorafenib, however, exacerbation of ITP had not occurred during bevacizumab containing treatment in the first-line setting at age of 66 years, which supports the hypothesis above.
Several multi-kinase inhibitors other than regorafenib also inhibit PDGF/PDGFR signaling, which may exacerbate ITP. Imatinib and sunitinib have been reported to induce immune thrombocytopenia (14,15), albeit that these studies did not investigate the possibility of pre-existing MSC dysfunction.
In conclusion, we report the first case of regorafenib-induced exacerbation of ITP in remission. This case report highlights the need for caution with regard to regorafenib treatment in cancer patients with concomitant ITP.
Acknowledgements
The authors would like to thank Dr Maki Kanzawa (Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan) for pathological diagnosis.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, KY, AH and NK made substantial contributions to the acquisition of the data. SK, YI and KY drafted the manuscript. AH, TK, YFuj, YFun, MT, NK, HMa and HMi made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Clinical and pathological findings. (A) Petechiae and purpura in the extremities on day 21. (B) Histopathologic findings of bone marrow examination. Trilineage hematopoiesis was maintained. The megakaryocyte count was slightly increased. Myelodysplasia or tumor metastasis were not observed. Scale bar, 100 µm. (C) Clinical course of treatment with regorafenib and immune thrombocytopenic purpura. Green arrows indicate 10 units of platelet transfusion. Prednisone (1 mg/kg/day) was administered from day 21 and reduced to 0.8 mg/kg/day on day 45. As the platelet count decreased, prednisone was again increased to 1 mg/kg/day on day 59.
Table I Laboratory data.
Variable Reference range Result
White blood cell count, 100/µl 33-86 50
Red blood cell count, 106/µl 3.86-4.92 2.90
Hemoglobin, g/dl 11.6-14.8 9.3
Hematocrit, % 35.1-44.4 28.4
Platelet count, 109/l 158-348 5
Immature platelet fraction, % 1-4.8 16.3
APTT, sec 25.0-38.0 31.6
PT, % 70.0-130.0 94.0
Fibrinogen, mg/dl 200-400 298
D dimer, µg/ml <1 4.1
Lactate dehydrogenase, U/l 124-222 615
Aspartate transaminase, U/l 13-30 32
Alanine aminotransferase, U/l 7-23 17
Total bilirubin, mg/ml 0.4-1.5 1.6
Creatinine, mg/dl 0.46-0.79 0.87
Blood urea nitrogen, mg/dl 8-20 26.8
C-reactive protein, mg/dl 0.00-0.14 1.55
PA IgG, ng/107 cells <27.6 176.8
50% complement hemolysis, U/ml 25-51 30.2
Complement C3, mg/dl 73-138 72
Complement C4, mg/dl 11-31 11
Antinuclear antibody, IF <40 320x
Antinuclear antibody pattern Centromere pattern
HIT antibody, U/ml <1 <0.6
IgG antibody for H. pylori, U/ml <10 3
Hepatitis B surface antigen, IU/ml <0.0049 <0.003
Hepatitis C virus antibodies, COI <0.99 0.04
HIV antibody/antigen combo assay, S/CO <0.99 0.12
APTT, activated partial thromboplastin time; COI, cutoff index; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; IF, indirect immunofluorescence; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PA IgG, platelet-associated IgG; PT, prothrombin time; S/CO, signal-to-cutoff. | Recovered | ReactionOutcome | CC BY-NC-ND | 33414911 | 18,800,829 | 2021-02 |
What was the outcome of reaction 'Thrombocytopenia'? | Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
Introduction
Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis [vascular endothelial growth factor receptor (VEGFR)1-3 and TIE2], tumor microenvironment (platelet-derived growth factor receptor β (PDGFRβ) and fibroblast growth factor receptor-1), and oncogenesis (c-KIT, RET, RAF-1 and B-RAF) (1). Based on this mode of action, regorafenib has a broad spectrum of toxicities (2). To date, however, few reports have focused on autoimmune adverse events.
Case report
The patient was a Japanese woman who had a past medical history of chronic immune thrombocytopenic purpura (ITP) which developed at the age of 38 years and was treated with steroid therapy, which resulted in remission for more than 20 years without medication. She was diagnosed with recurrent colon cancer at age 66 years, after primary surgery and adjuvant chemotherapy with capecitabine plus oxaliplatin. She had received three lines of palliative chemotherapy including fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab, panitumumab monotherapy and trifluridine/tipiracil. Platelet-associated IgG (PAIgG) was not detected when FOLFIRI plus bevacizumab was initiated. High-grade thrombocytopenia was not observed during treatment for recurrent colon cancer.
As a standard therapy in the late-line setting for recurrent/metastatic colorectal cancer (3,4), treatment with regorafenib 160 mg orally once daily for 21 days on/7-days off in a 28-day cycle was initiated at the age of 68 years. Platelet count was 167x109/l on day 1 but dropped to 61x109/l on day 15, and regorafenib was continued. On day 18, she vomited blood and presented at the emergency department. Laboratory examination showed severe thrombocytopenia with a platelet count of 5x109/l (Table I). Petechiae and purpura in the extremities and hemorrhagic blisters in the oral mucosa were also observed (Fig. 1A). Multiple platelet transfusions were given, but the response was poor. Further laboratory examination showed increased PAIgG of 176 ng (normal range <27.6 ng) and negative IgG for H. pylori and heparin-induced thrombocytopenia antibody (Table I). There were no clinical manifestations suggested systemic lupus erythematosus (SLE), such as arthritis, mucocutaneous involvement or Raynaud's phenomenon. Diagnostic criteria of SLE were not met. Bone marrow examination revealed normal hematopoiesis, slightly increased megakaryocytes and no myelodysplasia or tumor metastasis (Fig. 1B). There was no evidence of other risk factors for exacerbation of ITP, including a history of taking any dietary supplements or medications, or viral infections. Taken together, these findings strongly suggested regorafenib exacerbated ITP. Regorafenib was permanently discontinued, and prednisone 1 mg/kg/day was administrated on day 21. The hemorrhagic diathesis resolved one week later, and the severe thrombocytopenia gradually recovered (Fig. 1C).
Discussion
Thrombocytopenia associated with regorafenib is not rare. A meta-analysis reported incidences of all-grade and high-grade thrombocytopenia 22 and 3%, respectively (5). Inhibition of VEGFR is a potential mechanism of regorafenib-induced myelosuppression (6,7). Conventional thrombocytopenia is associated with bone marrow hypoplasia and responds to blood transfusion. In the present case, in contrast, normal hematopoiesis was maintained, and thrombocytopenia was refractory to platelet transfusion, which is likely explained by an autoimmune mechanism.
Diagnosis of ITP requires exclusion of a variety of potential causes for thrombocytopenia. Many conditions which cause decreased platelet production such as bone marrow damage, infiltration and replacement of the bone marrow due to malignancies and myelodysplastic syndromes were excluded by findings form the bone marrow biopsy in the present case. Drug-induced thrombocytopenia (DITP) is difficult to be distinguished from ITP. However, a history of ITP and unrecovered thrombocytopenia after discontinuation of regorafenib suggested more likely ITP than DITP (8). Moreover, a very low platelet count nadir less than 20x109/l, response to steroid and a positive anti-platelet autoantibody test are supposed to help precise diagnosis of ITP from expert opinions (9,10). Based on the above, the diagnosis of ITP was very likely.
ITP is an autoimmune disease which is characterized by platelet destruction associated with antibodies to platelets and megakaryocyte dysfunction (11). The pathogenesis of ITP is complicated and has not been fully clarified. Recent findings suggest that dysfunction of mesenchymal stem cells (MSCs) plays an important role (12,13). MSCs derived from ITP patients (MSCs-ITP) showed impaired self-proliferative capacity and the loss of immunosuppressive function. Interestingly, treatment of MSCs-ITP with PDGF-BB, a ligand of PDGFRβ, could reverse the defect of MSC-ITP in vitro (13). In this basis, regorafenib-induced inhibition of PDGF-BB/PDGFRβ signaling might trigger dysfunction of MSCs, resulting in the exacerbation of ITP. VEGF/VEGFR signaling is another important target of regorafenib, however, exacerbation of ITP had not occurred during bevacizumab containing treatment in the first-line setting at age of 66 years, which supports the hypothesis above.
Several multi-kinase inhibitors other than regorafenib also inhibit PDGF/PDGFR signaling, which may exacerbate ITP. Imatinib and sunitinib have been reported to induce immune thrombocytopenia (14,15), albeit that these studies did not investigate the possibility of pre-existing MSC dysfunction.
In conclusion, we report the first case of regorafenib-induced exacerbation of ITP in remission. This case report highlights the need for caution with regard to regorafenib treatment in cancer patients with concomitant ITP.
Acknowledgements
The authors would like to thank Dr Maki Kanzawa (Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan) for pathological diagnosis.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, KY, AH and NK made substantial contributions to the acquisition of the data. SK, YI and KY drafted the manuscript. AH, TK, YFuj, YFun, MT, NK, HMa and HMi made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Clinical and pathological findings. (A) Petechiae and purpura in the extremities on day 21. (B) Histopathologic findings of bone marrow examination. Trilineage hematopoiesis was maintained. The megakaryocyte count was slightly increased. Myelodysplasia or tumor metastasis were not observed. Scale bar, 100 µm. (C) Clinical course of treatment with regorafenib and immune thrombocytopenic purpura. Green arrows indicate 10 units of platelet transfusion. Prednisone (1 mg/kg/day) was administered from day 21 and reduced to 0.8 mg/kg/day on day 45. As the platelet count decreased, prednisone was again increased to 1 mg/kg/day on day 59.
Table I Laboratory data.
Variable Reference range Result
White blood cell count, 100/µl 33-86 50
Red blood cell count, 106/µl 3.86-4.92 2.90
Hemoglobin, g/dl 11.6-14.8 9.3
Hematocrit, % 35.1-44.4 28.4
Platelet count, 109/l 158-348 5
Immature platelet fraction, % 1-4.8 16.3
APTT, sec 25.0-38.0 31.6
PT, % 70.0-130.0 94.0
Fibrinogen, mg/dl 200-400 298
D dimer, µg/ml <1 4.1
Lactate dehydrogenase, U/l 124-222 615
Aspartate transaminase, U/l 13-30 32
Alanine aminotransferase, U/l 7-23 17
Total bilirubin, mg/ml 0.4-1.5 1.6
Creatinine, mg/dl 0.46-0.79 0.87
Blood urea nitrogen, mg/dl 8-20 26.8
C-reactive protein, mg/dl 0.00-0.14 1.55
PA IgG, ng/107 cells <27.6 176.8
50% complement hemolysis, U/ml 25-51 30.2
Complement C3, mg/dl 73-138 72
Complement C4, mg/dl 11-31 11
Antinuclear antibody, IF <40 320x
Antinuclear antibody pattern Centromere pattern
HIT antibody, U/ml <1 <0.6
IgG antibody for H. pylori, U/ml <10 3
Hepatitis B surface antigen, IU/ml <0.0049 <0.003
Hepatitis C virus antibodies, COI <0.99 0.04
HIV antibody/antigen combo assay, S/CO <0.99 0.12
APTT, activated partial thromboplastin time; COI, cutoff index; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; IF, indirect immunofluorescence; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PA IgG, platelet-associated IgG; PT, prothrombin time; S/CO, signal-to-cutoff. | Recovered | ReactionOutcome | CC BY-NC-ND | 33414911 | 18,800,829 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | ACYCLOVIR, AMIODARONE, AMOXICILLIN\CLAVULANIC ACID, ATORVASTATIN, DAPTOMYCIN, HYDROXYCHLOROQUINE, IMIPENEM, MEROPENEM, PANTOPRAZOLE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISOLONE, TIGECYCLINE, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY | 33419393 | 18,857,967 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrial fibrillation'. | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | ACYCLOVIR, AMIODARONE, AMOXICILLIN\CLAVULANIC ACID, ATORVASTATIN, DAPTOMYCIN, HYDROXYCHLOROQUINE, IMIPENEM, MEROPENEM, PANTOPRAZOLE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISOLONE, TIGECYCLINE, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY | 33419393 | 18,857,967 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic kidney disease'. | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | ACYCLOVIR, AMIODARONE, AMOXICILLIN\CLAVULANIC ACID, ATORVASTATIN, DAPTOMYCIN, HYDROXYCHLOROQUINE, IMIPENEM, MEROPENEM, PANTOPRAZOLE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, TIGECYCLINE, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY | 33419393 | 18,855,984 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ileus paralytic'. | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | ACYCLOVIR, AMIODARONE, AMOXICILLIN\CLAVULANIC ACID, ATORVASTATIN, DAPTOMYCIN, HYDROXYCHLOROQUINE, IMIPENEM, MEROPENEM, PANTOPRAZOLE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISOLONE, TIGECYCLINE, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY | 33419393 | 18,857,967 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'. | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | ACYCLOVIR, AMIODARONE, AMOXICILLIN\CLAVULANIC ACID, ATORVASTATIN, DAPTOMYCIN, HYDROXYCHLOROQUINE, IMIPENEM, MEROPENEM, PANTOPRAZOLE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, TIGECYCLINE, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY | 33419393 | 18,855,984 | 2021-01-08 |
What was the dosage of drug 'DAPTOMYCIN'? | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | 40 mg (milligrams). | DrugDosage | CC BY | 33419393 | 18,857,967 | 2021-01-08 |
What was the dosage of drug 'VANCOMYCIN'? | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | 40 mg (milligrams). | DrugDosage | CC BY | 33419393 | 18,857,967 | 2021-01-08 |
What was the outcome of reaction 'Acute kidney injury'? | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | Recovering | ReactionOutcome | CC BY | 33419393 | 18,857,967 | 2021-01-08 |
What was the outcome of reaction 'Haemolytic anaemia'? | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | Recovering | ReactionOutcome | CC BY | 33419393 | 18,855,984 | 2021-01-08 |
What was the outcome of reaction 'Metabolic acidosis'? | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | Recovering | ReactionOutcome | CC BY | 33419393 | 18,855,984 | 2021-01-08 |
What was the outcome of reaction 'Rash maculo-papular'? | Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.
The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.
Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
Background
Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required [1–6]. Case reports and autopsy series have revealed that most patients with COVID-19-associated AKI have evidence of acute tubular injury (ATI) and/or acute tubular necrosis (ATN) - not unexpected in critically ill patients [7–9]. A mild associated interstitial infiltrate may be present [10]. Other biopsy findings have included collapsing glomerulopathy (associated with African ancestry and a high-risk APOL1 genotype [11, 12], thrombotic microangiopathy, and diverse underlying kidney diseases [8, 13]. Kidney infarction has also been reported [14]. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney remains controversial [8, 10, 13]. Recent description of viral particles in the tubular epithelium may support this possibility, although the clinical significance of this remains unknown [15].
At present, the management of AKI is supportive. During the first wave of SARS Cov2, around 1 in 4 patients with severe COVID and intubated the intensive care unit (ICU) require dialysis [6, 16]. Mortality rates are higher in patients with hospital-acquired AKI compared with community-acquired AKI associated with COVID-19 [4]. Ongoing vigilance is therefore required throughout the hospital course. Many patients, given the severity of illness, receive multiple medications including a variety of antibiotics, and increasingly potential therapies are being tested with encouraging results. Patients may therefore be expected to be at risk of drug-associated hypersensitivity [17, 18]. Initially the use of corticosteroids was not routinely advocated, however recent data showed a reduction in 28-day mortality when used in severe COVID-19 [19]. How these therapies may impact AKI and renal recovery in patients with COVID-19 remains unknown. Here we report a patient with severe COVID-19 who had developed AKI in the setting of multiorgan dysfunction, a skin rash and hemolysis. After nephrology consultation, a kidney biopsy was performed, which led to a change in management and patient improvement.
Case presentation
A 62-year-old Caucasian man presented with symptoms of cough, fever, myalgia and chills. Symptoms had begun 6 days prior to admission. He had tested positive for SARS-CoV-2 by Xpert Xpress SaRS-CoV-2 (Cepheid, Dx System Version 4.8) three days after symptom onset. His past medical history was unremarkable except for hyperlipidemia treated with atorvastatin 40 mg daily. No allergies were reported, the patient did not smoke, drink alcohol or use illicit substances. Kidney function was normal on admission.
Computed tomography (CT) scan of the chest, abdomen and pelvis excluded pulmonary emboli and showed diffuse bilateral ground-glass infiltrates of the lungs with associated lymphadenopathy, moderate pleural effusions, normal-sized and -shaped kidneys with adequate perfusion and without cortical defects.
Two days after admission the patient required intubation due to acute respiratory distress syndrome (ARDS). He was managed with prone positioning and was initiated on hydroxychloroquine after exclusion of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Antibiotic therapy with amoxicillin-clavulanate was given empirically assuming bacterial superinfection of viral pneumonia. His clinical condition worsened with the development of atrial fibrillation, AKI, paralytic ileus, hemolytic anemia and a maculopapular rash on the trunk and lower extremities.
The chronologic sequence of medications and clinical events are highlighted in Fig. 1. Laboratory results are shown in Table 1. Details of affected organ systems, diagnostics and therapies are listed in Table 2. Fig. 1 Timeline
Table 1 Laboratory results
Laboratory Test Reference range Admission to hospital
(Day 0)a Day of transfer to tertiary center
(Day 8) a Hemolytic anemia
(Day 24)a Renal consult
(Day 26)a Day of Biopsy
(Day 32)a Day of transfer
(Day 48)a
BLOOD ANALYSIS
Urea, mmol/l 2.76–8.07 - 37.4 CVVHD CVVHD CVVHD 29.8
Creatinine, umol/l 59–104 87 498 CVVHD CVVHD CVVHD 130
Albumin, g/l 39.7–49.5 - 18.5 19.1 25.8 19.8 22.7
CRP, mg/l < 5 223 310 339 150 201 27.1
PCT, ng/ml < 0.5 0.29 2.42 9.13 3.71 5.05 2.56
Ferritin, ug/l 30–400 - > 11,063 - 2505 4646 3480
D-dimer, mg/l < 0.5 1.38 3.98 2.55 2.77 2.63 -
IL-6, pg/ml < 7 - - - - 56.2 -
AST, U/l < 40 60 252 49 68 73 38
ALT, U/l < 50 78 146 43 35 47 78
Bilirubin totally, umol/l 3.4–17 - 15.1 29.4 17.3 24 -
Bilirubin indirect, umol/l < 12.8 - 0.9 3.9 - - -
Hemoglobin, g/l 140–180 138 91 69 72 78 71
Schistocytes - + +
Platelet count 139–335 10E3/ul 241 612 598 501 298 513
Haptoglobin, g/l 0.3-2.0 - - < 0.1 < 0.1 < 0.1 0.91
LDH, U/l 240–480 770 999 1173 1125 1109 636
Coombs test Positive/negative - - - negative - -
WBC count 3.5–10 10E3/ml 10 8.6 36.5 25.8 23.8 12.9
Eosinophils 0.08–0.36 10E3/ul 0.01 0.11 0.51 0.12 1.10 0.68
URINE ANALYSIS
Fractional excretion of Urea (%) - 46.8 - - - -
Urine PCR, mg/mmol < 20 - 72.6 - - - -
Urine ACR,
mg/mmol
< 3 - 5.3 - - - -
Urine,
red blood cells, /ul
< 23 10 388 - 13.6 829 3
(03.05.)
Urine, leucocytes, /ul < 25 15 8 - 5.1 29.1 1
(03.05)
Abbreviations: CRP C-reactive proteine, PCT procalcitonin, IL-6 interleukin 6, AST aspartate amino transferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, WBC white blood cells, PCR protein/creatinine ratio, ACR albumine/creatinine ratio
a+/- 3 days
Table 2 Affected organ systems and therapeutic measures
Affected organ system / Medical problem Diagnostics / Results Therapy
Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio as deep as 80 CT scan thorax / bilateral ground-glass infiltrates of the lungs, pleural effusions Prone positioning
Nitric oxide therapy
Co-infections causing pneumonia and sepsis - ventilator associated pneumonia with Proteus vulgaris and sepsis
- viral pneumonia with Herpes simplex virus 1
- catheter infection with Staphylococcus epidermidis
Thoracic drain
Antimicrobial therapy
Acute kidney injury (AKI) Kidney biopsy / granulomatous tubulointerstitial nephritis Continous veno-venous hemodiafiltration
Discontinuation of beta-lactams & proton pump inhibitor
Corticosteroid therapy
Encephalopathy - CT and MRI head / multiple intracranial microhemorrhages
- EEG/ no epileptic activity
Termination of unnecessary medication
Temporary reduction of anticoagulation
Physiotherapy
Hemodynamic instability ECG / Intermittent atrial fibrillation
Echocardiography / left ventricular function within normal limits
Vasopressors
Amiodarone
Electric cardioversion
Therapeutic anticoagulation
Hemolytic anemia Laboratory testing/ Coombs test negative, ADAMTS 13 normal,
Blood immunophenotyping/ no evidence of paroxysmal nocturnal hemoglobinuria
Transfusion of packed red blood cells
Discontinuation of imipenem and amiodarone
Corticosteroid therapy
Local bleeding after tracheostomy without hemodynamic instability Clinical examination Transfusion of packed red blood cells
Mechanical compression
Critical illness polyneuropathy Diffuse, symmetric, flaccid paresis, muscle weakness Physiotherapy, discharge to rehabilitation facility
Hepatopathy Hepatitis B and C negative
No cholestasis on imaging
Reduction of hepatotoxic medication
Maculopapular rash Skin biopsy / dermoepidermal junction with focal vacuolization; lymphocytic infiltrates and rare eosinophils within the corium, discrete vasculitic changes and extravasates of erythrocytes; consistent with drug-induced exanthema; negative for SARS-CoV-2 Corticosteroids topically and systemically
A maculo-papular skin rash developed on day 7 after admission. Severe AKI with oliguria (AKIN 3), consecutive fluid overload and metabolic acidosis necessitated initiation of continuous veno-venous hemodiafiltration (CVVHDF) on day 9. Peak creatinine was 519 umol/L, urinalysis showed minimal proteinuria and microscopic hematuria. Proteinuria subsequently increased significantly and microscopic hematuria persisted, urine leucocytes were persistently within the normal range. (Table 1).
Several days after initiation of CVVHDF (on day 24) the patient developed severe microangiopathic hemolytic anemia, Coombs negative, which was transfusion dependent. Serologic screening was negative for HIV, hepatitis B and C virus infection; anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies, anti-cardiolipin antibodies and complement levels were normal. Eosinophils were initially not significantly elevated. There was no evidence of urinary obstruction or rhabdomyolysis. Echocardiogram showed preserved cardiac function.
Differential diagnosis of the AKI included acute tubular injury (ATI) due to hemodynamic instability; sepsis-associated AKI; ATI with pigmented tubular casts as a consequence of hemolysis; thrombotic microangiopathy - given the ongoing severe hemolysis with schistocytes on peripheral smear (despite lack of overt thrombocytopenia); collapsing glomerulopathy - given the large rise in proteinuria,; and acute interstitial nephritis associated with antibiotics - given concurrent skin rash, although peripheral eosinophilia and leucocyturia were not marked. In the absence of improvement of kidney function a transcutaneous renal biopsy was performed while the patient was proned in ICU, 32 days after admission.
Light microscopy revealed 34 mostly normal glomeruli. Few glomeruli were mildly congested, without thrombi. There was diffuse interstitial edema and focal infiltrates with lymphocytes, histiocytes, rare plasma cells, neutrophils and eosinophils. Multiple non-caseating granulomas mostly consisting of lymphocytes and epithelioid histiocytes (Fig. 2) were present. There was very mild tubulitis with rare lymphocytes in the tubular epithelium. Many tubules had a dilated lumen, flattened epithelium and loss of brush border. Some had fine, isometric vacuolization of the cytoplasm. Rare lumina contained finely granular, mostly eosinophilic and very rare brownish casts only partially positive for hemoglobin in a few tubules. Some peritubular capillaries contained mononuclear cells, but no erythrocyte aggregation. There was mild arteriolar hyalinosis and arteriosclerosis, but no thrombi or vasculitis. Immunhistochemistry showed only trace IgM, Kappa and Lambda in the mesangium. IgG, IgA, C3 and C1q were negative in the glomeruli. Electron microscopy revealed myelin figures in the cytoplasm of a few parietal epithelia. No definite viral particles were detected. Fig. 2 a: Kidney biopsy with interstitial infiltrates of mostly lymphocytes, histiocytes and plasma cells and a noncaseating granuloma (arrowheads) (PAS, Periodic acid-Schiff reaction). b: Detail of another peritubular granuloma with lymphocytes and epithelioid macrophages (arrows) (PAS)
The biopsy was consistent with granulomatous tubulointerstitial nephritis, acute tubular injury and regeneration. There was no evidence of renal thrombotic microangiopathy, collapsing glomerulopathy or vasculitis.
Mycobacterium tuberculosis infection as excluded and confirmed by negative cultures of urine and tracheal secretions. Serology for Sjogren’s Syndrome was negative. Sarcoidosis was considered clinically unlikely, despite thoracic lymphadenopathy which was interpreted as consistent with severe SARS Cov2 pneumonia. The ionized calcium levels were normal or low during the ICU stay. Angiotensin converting enzyme and Interleukin-2 levels were however not measured. The biopsy findings could not explain the proteinuria, which was interpreted as a consequence of kidney injury and profound inflammation associated with SARS Cov2 infection.
Given that a medication reaction was a potential cause for kidney biopsy findings as well as for the rash and the hemolysis, a multidisciplinary decision was taken to stop ß-lactams, amiodarone and pantoprazole and to begin methylprednisolone 60 mg daily on day 37 (Fig. 1). 47 days after admission urine output began to improve and CVVHDF was discontinued. The hemolysis resolved, the skin rash improved.
On transfer to neurorehabilitation 48 days after admission, the patient was tetraparetic due to critical illness polyneuropathy but alert and able to follow simple commands, he had tracheostomy in place and was breathing spontaneously with little support. The course of rehabilitation showed progressive improvement of kidney function (Fig. 1). The estimated GFR two months post-discharge was 43 ml/min/1,73 m2 suggesting a likely transition to chronic kidney disease.
Discussion and conclusions
The underlying pathophysiology of impaired kidney function in patients suffering from COVID-19 is likely complex and multifactorial and to date incompletely understood [8, 13, 20]. Virus-induced sepsis with hemodynamic instability and renal hypoperfusion may promote ATI [9, 21, 22]. Upregulation of proinflammatory cytokines and chemokines in the setting of sepsis, generally described as “cytokine storm”, may trigger multiorgan failure including ATI [20, 23, 24]; SARS-CoV-2-associated hypercoagulability may aggravate endothelial dysfunction leading to microangiopathy and collapsing glomerulopathy [25–27]. SARS-CoV-2 RNA has been isolated in urine and viral particles have been demonstrated in post-mortem kidney tissue by some authors but not others [9, 10, 15] suggesting possible renal tropism of the virus, although others have failed to find viral RNA in kidney tissue by in-situ hybridization or RT-PCR in kidney biopsies [28, 13]. Internalisation of coronavirus into kidney tissue may potentially be mediated through the angiotensin-converting enzyme 2 (ACE2) receptor [9, 20, 29].
We report a case of GIN in a patient with COVID-19 who required prolonged CVVHDF. Clinical evidence of thrombotic microangiopathy on the background of oliguric AKI, proteinuria and hematuria had prompted the kidney biopsy. Surprisingly no evidence of thrombotic microangiopathy or significant pigmented tubular casts was found. Interestingly, the patient had no evidence of leukocyturia and no significant eosinophilia prior to biopsy, however significant eosinophilia was observed on the day of biopsy (Table 1). The patient had no prior history of medication allergies or skin rashes, but histopathologic findings of skin biopsy were in concordance with an allergic, drug-induced skin reaction (Table 2). Consistent with the possibility of a drug-induced etiology, AKI developed at the same time as the skin rash. The rash had been presumed to be related to Amoxicillin, which had been discontinued. However our patient subsequently received various other beta-lactam antibiotics as illustrated in Fig. 1. Skin rashes are common in patients with COVID-19, with maculo-papular rashes being the most frequent[30]. A drug-induced etiology is often hypothesized as these patients tend to be sicker and thus receive multiple medications compared with patients with other rashes.
The patient described here also developed severe coombs-negative hemolytic anemia with schistocytes on peripheral blood smear. Criteria for thrombocytopenia were not met, but platelet counts did drop by approximately 60%. Work-up excluded thrombotic thrombocytopenic purpura (normal serum-ADAMTS19 activity), paroxysmal nocturnal hematuria or glucose-6-phosphate-deficiency. There was no evidence of hereditary erythrocyte membrane disorder or hemoglobinopathy. An association between hemolytic anemia and interstitial nephritis has been described [31], although in general these cases had a positive Coombs test indicating immune-mediated hemolysis induced by medication. Drug-induced immune-mediated hemolysis with a negative Coombs test, potentially falsely negative due to the severity of the hemolysis and number of transfusions, has however been reported [32]. We were unable to measure specific anti-antibiotic antibodies to test this hypothesis and cannot exclude drug-induced hemolysis. In recent months several cases of auto-immune hemolytic anemias (Coombs positive) in patients with COVID-19 have been described, but most appear to have been associated with underlying diseases and severe AKI was not reported. Of note direct association with COVID itself was postulated in 2 cases [33–35]. Importantly, most of these patients responded favorably to steroid therapy, as did the patient reported here. The presence of schistocytes in the peripheral blood smear in our patient suggests the presence of a microangiopathy, which we were not able to detect in the kidney biopsy. As SARS-CoV-2 infection may be associated with endothelial injury [20, 25], however, the hemolysis may have reflected microvascular injury elsewhere.
GIN is rarely observed in kidney biopsies (< 1% of native kidney biopsies), and the differential diagnosis is broad and challenging [36]. Apart from the usual suspects including medications (especially antibiotics and nonsteroidal anti-inflammatory drugs) and autoimmune disorders (i.e. vasculitis, especially granulomatosis with polyangiitis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU)-syndrome), microorganisms such as mycobacteria and fungi have been implicated [37]. We could not find evidence of these diseases in the current case. In the case presented here, tuberculosis was excluded with negative cultures and autoimmune disorders were excluded with negative serologies. Sarcoidosis could not be completely ruled out, but given the lack of sharply defined granulomas in the biopsy and in the absence of Schaumann bodies, the histology was most consistent with a drug-induced cause for the GIN. A follow-up serum calcium after hospital discharge, when the patient was no longer on steroids remained within the normal range. Myelin bodies described in the biopsy were sparse, not consistent with a diagnosis of Fabry’s Disease, and were more likely associated with hydroxychloroquine or amiodarone use. Both medications were discontinued. A further differential diagnosis of GIN in our patient included secondary hemophagocytic lymphohistiocytosis (sHLH), which has been associated with COVID-19 [38]. Also known as macrophage activation syndrome, it is a systemic inflammatory syndrome, manifest by a fulminant hypercytokinemia [20, 39, 40]. The clinical picture is broad including fever, hepatosplenomegaly, hepatobiliary dysfunction and pulmonary involvement (including ARDS). Renal injury and cutaneous rash – as present in our patient – may also occur [39]. Laboratory abnormalities include cytopenias, coagulopathy, altered liver function test, hypertriglyceridemia and hyperferritinemia [39]. A bone marrow aspirate was not performed, but given the multiorgan dysfunction and the very high ferritin levels sHLH could not be entirely excluded. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated with hydroxychloroquine or azithromycin has been reported in a patient with COVID-19 [41]. This patient had mild renal dysfunction and responded to corticosteroid therapy. DRESS syndrome was unlikely in our patient however, given the absence of significant eosinophilia and only transient elevation in liver enzymes.
Taken together, a medication-related etiology of GIN leading to AKI, and possibly to hemolysis and the skin rash, seems most likely here. Whether and how the background inflammatory milieu of COVID-19 might have modulated the disease phenotype or independently contributed to the findings remains unclear. The rapidity of the clinical response in terms of improvement of kidney function and hemolysis suggests a benefit from corticosteroid therapy in this patient. At the time of treatment, corticosteroid therapy was not routinely recommended in COVID-19, and there was even some hesitation about their use. The kidney biopsy findings however prompted in-depth multi-disciplinary discussion and re-review of all the clinical findings and led to a decision to initiate corticosteroid therapy.
Interstitial infiltrates have not commonly been described in the published kidney biopsy series from patients with COVID-19 [8, 10, 13]. As most patients with severe COVID-19 in the ICU likely receive multiple medications known to be associated with interstitial nephritis, this finding may be somewhat surprising. Discussion of the risk of drug reactions in the literature has thus far focused on potential specific therapeutic agents for COVID-19 itself [17, 18], although many other medications are used simultaneously given the severity of illness (Fig. 1). The risk of medication-associated adverse reactions may therefore be more clinically relevant than recognized. Based on the findings in this case, we suggest that this diagnosis should be considered more frequently as a potential indication for a kidney biopsy as there may be important therapeutic consequences.
Given the clinically unexpected finding of GIN in this case and the favorable response to treatment, we suggest that nephrology consultation and kidney biopsy are of value in better understanding the pathophysiology of renal involvement in patients suffering from SARS-CoV2 infection. Even late in the course a kidney biopsy may lead to changes in therapy which can positively impact outcomes.
Abbreviations
COVID-19 Coronavirus disease 19
AKI Acute kidney injury
SARS-CoV-2 .
ATI Acute tubular injury
ICU Intensive care unit
CT Computed tomography
ARDS Acute respiratory distress syndrome
G6PD Glucose-6-phosphate dehydrogenase
CVVHDF Continuous veno-venous hemodiafiltration
DRESS Drug reaction with eosinophilia and systemic symptoms
sHLH Secondary hemophagocytic lymphohistiocytosis
GIN Granulomatous interstitial nephritis
CRP C-reactive proteine
PCT Procalcitonin
IL-6 Interleukin 6
AST Aspartate amino transferase
ALT Alanine aminotransferase
LDH Lactate dehydrogenase
WBC White blood cells
PCR Protein/creatinine ratio
ACR Albumine/creatinine ratio
Acknowledgements
Dr. Kathrin Fausch, Dr. Reto Venzin for valuable contribution to clinical discussions.
Authors' contributions
KS, MK, PG all actively managed the patient and wrote the first draft of the manuscript, AG reviewed and reported on the kidney biopsy and prepared the related images and text, TF, VL, AC and KH provided clinical consultation and contributed to manuscript writing and all authors contributed to manuscript review. KS and MK contributed equally as ‘first authors’. All authors have read and approved the manuscript.
Funding
No funding was required for this case report.
Availability of data and materials
Data are displayed in the text, tables and figures. The raw data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
not applicable.
Consent for publication
Written informed consent for publication of their clinical details and clinical images was obtained from the patient’s legal substitute on 05/15/2020. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare no conflicts of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Katarzyna Szajek and Marie-Elisabeth Kajdi contributed equally to this work. | Recovering | ReactionOutcome | CC BY | 33419393 | 18,855,984 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'. | Calculating the dose of cisplatin that is actually utilized in hyperthermic intraperitoneal chemotherapy among ovarian cancer patients.
BACKGROUND
Hyperthermic intraperitoneal chemotherapy (HIPEC) is an important treatment for ovarian cancer. A certain portion of cisplatin exits the body via the perfusate at the end of HIPEC, so full-dose utilization cannot be achieved. Herein, we sought to explore how much cisplatin is actually utilized and its prognostic influence.
METHODS
Cisplatin (70 mg/m2) was given at 43 °C for 90 min. The actually utilized dose (AD) of cisplatin was calculated using the following formula: AD (mg) = total dose (TD) (mg)-losing dose (LD) (mg); LD = volume (ml) of the perfusate (VPretained) that was retained in the HIPEC treatment system at the end of HIPEC * concentration of cisplatin in the perfusate (mg/ml).
RESULTS
Sixty-two ovarian cancer patients were included. The median TD, median LD and median AD were 95 mg, 20.7 mg and 75.8 mg, respectively. The utility rate of cisplatin (AD/TD ratio) was 79.2%. On simple linear regression analysis, the TD and VPretained were found to significantly predict the AD. Based on these two factors, multiple linear regression analysis was conducted, and a significant regression equation was formulated [F (2, 59) = 71.419, P < 0.0001]: predicted AD (mg) = 30.079 + 0.667 TD (mg) - 0.010 VPretained (ml) (adjusted R2 = 0.698). In Cox regression analysis, AD was not noted to be associated with progression free survival or overall survival.
CONCLUSIONS
For ovarian cancer patients who receive cisplatin for HIPEC at 43 °C, the AD of cisplatin can be predicted using a regression equation and it has no prognostic impact.
Introduction
Ovarian cancer is the deadliest gynecologic cancer and is usually diagnosed after the cancer has spread beyond the ovary [1]. Primary debulking surgery (PDS) combined with chemotherapy has been the first-line treatment for ovarian cancer patients. However, even among patients without evidence of disease following treatment, 70% experience recurrence within the subsequent 3 years, and almost 80% succumb to their disease [2].
Because of a clear tendency to develop peritoneal metastasis, attempts to improve outcomes for this patient population have prompted the investigation of intraperitoneal chemotherapy (IPC), and its effect has been validated [3]. IPC can also be delivered under hyperthermic conditions, which is termed hyperthermic intraperitoneal chemotherapy (HIPEC). An increasing number of studies have shown a survival benefit associated with HIPEC among ovarian cancer patients [4–8]. Based on this evidence, HIPEC has been recommended in the National Comprehensive Cancer Network (NCCN) guidelines for patients receiving interval debulking surgery (IDS) [9]. In the China Anti-Cancer Association (CACA) guidelines, HIPEC is recommended as an adjuvant treatment for gynecologic cancer patients with peritoneal carcinomatosis; currently, it has been a publicly approved therapy in China and its costs are covered by insurance plans [10].
Owing to a favorable peritoneal plasma gradient, cisplatin is the preferred agent for IPC [11]. The addition of hyperthermia to intraperitoneal cisplatin can result in synergistic effects, thereby enhancing cytotoxicity [12]. Therefore, cisplatin is also the most commonly used drug in HIPEC [13]. A noteworthy observation in clinical practice is that a certain portion of cisplatin exits the body via the perfusate at the end of treatment, so full cisplatin uptake cannot be achieved. Previous investigations have explored the pharmacokinetic features of cisplatin in HIPEC [14–16]. However, no investigator could provide a clear-cut answer to the following critical question: how much cisplatin is actually utilized by a patient during HIPEC? Accordingly, it is unclear whether the amount of cisplatin depletion adversely affects therapeutic effect. We herein conducted a study to predict the actual uptake dose of cisplatin based on clinical variables that are easy to obtain and investigate its prognostic effect. From a clinical perspective, we believe that our findings are conducive to optimizing the dose planning and schedule of cisplatin in HIPEC.
Materials and methods
After Institutional Review Board approval was obtained (Approval No. SYSEC-KY-KS-2020-046), a retrospective chart review was conducted. Ovarian cancer patients who received cisplatin for HIPEC between 2016 and 2018 were identified. Patients who were considered for HIPEC underwent detailed counseling with regard to the potential risks and benefits within the context of previously published clinical trials and guidelines. All patients provided signed informed consent. Data from patients who received intravenous platinum within 2 weeks before HIPEC and patients who did not undergo the complete HIPEC procedure were excluded.
Surgical complexity of the debulking surgery was based on a complexity score which was calculated using a published scoring system [17]. At the end of cytoreduction, four tubes were placed (two in the bilateral subdiaphragmatic space for use as inlet tubes and two in the pelvic cavity for use as an outlet tubes) before closing the incision, which were used to administrate HIPEC. HIPEC was given following surgery using a close technique. A high-precision hyperthermic intraperitoneal perfusion treatment system with a precision of ±0.10 °C for temperature control and ± 5% for flow control (approved by the State Food Drug Administration of China, approval no. 2009–3,260,924) was utilized. Cisplatin was given at a dose of 70 mg per square meter and was added to 3000–5000 ml of saline solution. The perfusate was heated and circulated at a flow rate of 300–500 ml/min. The perfusion velocity was adjusted to ensure that the entire abdomen was exposed to the perfusate (the initial velocity was 300 ml/min and increased gradually until the patient felt floated or until a flow rate of 500 ml/min was achieved). An intraabdominal temperature of 43 °C was maintained and measured by the treatment system using temperature monitoring probes in the infusion and outflow catheters. The HIPEC procedure took 90 min in total, consisting of a 30 min preheating period and a 60 min perfusion period. All patients received continuous intravenous fluids to assure adequate hydration. During the treatment, vital signs and urine output were monitored continually. After HIPEC treatment, the perfusate retained in the treatment system and in the tubes was collected after removing the tubes, and then the volume was measured. Thereafter, a portion of the perfusate was stored at − 80 °C and analyzed within 3 weeks. Perfusate collecting and volume assessment have been integrated into routine clinical care in our institution since 2015. Cisplatin concentrations in the perfusate were measured by inductively coupled plasma mass spectrometry (ICP-MS; PerkinElmer, America). The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0 was used to grade HIPEC-related adverse events (AEs) that presented within 3 weeks of HIPEC.
The Kolmogorov-Smirnov test was used to determine the distribution of continuous variables. Student’s t test was used to compare normally distributed continuous variables, whereas the Mann-Whitney U test was used to compare nonnormally distributed variables. The following equation was applied to calculate the quantity of cisplatin uptake during HIPEC:
Actually utilized doseADmg=total doseTDmg−losing doseLDmg TD=70mg/m2∗body surface aream2the resultingTDwas rounded to the closest integer LD=volumemlof the perfusateVPretainedthat was retained in the treatment systemattheendof HIPEC∗concentration of cisplatin in the perfusatemg/ml.
To explore associations between the AD and potential clinical variables, linear regression analysis was conducted. These variables included patient age, body mass index (BMI), TD, VPretained and serum levels of creatinine and albumin prior to HIPEC. Assumptions that underpin linear regression were confirmed as described previously. The final regression equation was established using a multiple linear regression model with the enter method. Variables with P values < 0.05 in the simple linear regression analysis were entered into the multiple linear regression analysis. Cox proportional hazards regression model was used to explore the prognostic influence of AD. Statistical tests were two-sided, and a P value < 0.05 was considered statistically significant. All data analyses were performed with SPSS 20.0 for Windows (SPSS, Inc., Chicago, IL).
Results
A total of 62 patients were included in the final analysis. Table 1 summarizes the patient demographics and clinical characteristics. Because of massive ascites and pleural effusion, six patients had restricted activity (9.7%). Before HIPEC, abnormal serum creatinine levels were noted in one patient (1.6%) who had an elevated serum creatinine level (137 μmol/l) since diagnosis. This patient had no complaints and denied a history of kidney disease. Repeated creatinine tests and further kidney function evaluations were performed, but no evidence of acute or chronic kidney injury was identified. Then, the mean serum creatinine value (159 μmol/l) was used for the analysis. Of our cohort, 44 patients (71.0%) received HIPEC following PDS, while 18 patients (29.0%) received HIPEC following IDS.
Table 1 Demographic and clinical characteristics of patients
Characteristic
Age (years), median (range) 51 (18, 76)
BMI (kg/m2), median (range) 22.1 (15.8, 34.8)
Body surface area (m2), median (range) 1.42 (1.21, 1.71)
ECOG performance status (%)
Normal activity 56 (90.3)
Restricted activity 6 (9.7)
Histology (%)
High grade serous adenocarcinoma 46 (74.2)
Mucinous adenocarcinoma 3 (4.8)
High grade endometrioid adenocarcinoma 3 (4.8)
Clear cell carcinoma 5 (8.1)
Malignant mixed mullerian tumor 5 (8.1)
FIGO stage (%)
IIIC 43 (69.4)
IV 19 (30.7)
Surgical treatment (%)
Primary debulking surgery 44 (71.0)
Interval debulking surgery 18 (29.0)
Gross residual disease (%)
Yes 43 (69.4)
No 19 (30.7)
Surgical complexity (%)
Low 5 (8.1)
Moderate 40 (64.5)
High 17 (27.4)
ICU stay (%)
Yes 2 (3.2)
No 60 (96.8)
Serum creatinine (umol/L), median (range)
Prior to HIPEC 63.5 (49, 159)
Following HIPEC 62.0 (48, 149)
Serum albumin (g/l), median (range)
Prior to HIPEC 25 (15, 36)
Following HIPEC 22 (15, 30)
BMI Body mass index, ECOG Eastern cooperative oncology group, HIPEC Hyperthermic intraperitoneal chemotherapy, ICU Intensive care unit
Table 2 shows variables that were related to the cisplatin dose. The median TD and LD values were 95 mg (range: 85–120 mg) and 20.7 mg (range: 9.6–37.8 mg), respectively. Based on the formulation mentioned above, the median calculated AD value was 75.8 mg (range: 48.3–92.4 mg). The AD/TD ratio refers to the utility rate of cisplatin, and the median percentage was 79.2% (range: 62.2–90.4%).
Table 2 Hyperthermic intraperitoneal chemotherapy related parameters
Parameter
TD (mg), median (range) 95 (85, 120)
Perfusate at the end of HIPEC
Volume (ml), median (range) 1835 (1050, 2670)
Concentration of cisplatin (μg/ml), median (range) 11.3 (6.6, 19.4)
LD (mg), median (range) 20.7 (9.6, 37.8)
AD (mg), median (range) 75.8 (48.3, 92.4)
Utility rate of cisplatina (%), median (range) 79.2 (62.2, 90.4)
AD Actually utilized dose, LD Losing dose, HIPEC Hyperthermic intraperitoneal chemotherapy, TD Total dose;
aUtility rate of cisplatin = actually used dose of cisplatin (mg)/ total dose of cisplatin (mg)
The results of the linear regression analysis are summarized in Table 3. The TD and VPretained had a linear relationship with the AD (Fig. 1a and b) and were able to significantly predict the AD on simple linear regression analysis. Based on these two factors, multiple linear regression analysis was conducted, and a significant regression equation was formulated [F (2, 59) = 71.419, P < 0.0001], with an R2 of 0.708. The formula was as follows: predicted AD (mg) = 30.079 + 0.667 TD (mg) – 0.010 VPretained (ml). Therefore, when maintaining all other variables constant, the AD increased 0.667 mg for each milligram increase in the TD, while the AD decreased 0.010 mg for each milliliter increase in the VPretained. Both the TD and VPretained were significant predictors for the AD. The TD and VPretained accounted for 69.8% (adjusted R2 = 0.698) of the explained variability in the AD. Figure 1c illustrates scatter plots of the actual vs predicted AD values.
Table 3 Linear regression model results for actually utilized dose of cisplatin
β 95% CI for β P value β 95% CI for β P value
Age (years) −0.012 −0.169, 0.146 0.881 – – –
BMI (kg/m2) −0.117 −0.705, 0.472 0.693 – – –
Serum creatinine prior to HIPEC (umol/l) 0.013 −0.103, 0.129 0.822 – – –
Serum albumin (g/l) prior to HIPEC 0.078 −0.308, 0.464 0.689 – – –
TD (mg) 0.777 0.554, 1.000 < 0.001 0.667 0.500, 0.833 < 0.001
VPretained (ml) −0.012 −0.016, − 0.008 < 0.001 0.010 −0.013, − 0.007 < 0.001
BMI Body mass index, HIPEC Hyperthermic intraperitoneal chemotherapy, TD Total dose, VPretained Volume (ml) of the perfusate that was retained in the treatment system at the end of hyperthermic intraperitoneal chemotherapy;
Fig. 1 a. The linear relationship between actually utilized dose of cisplatin (mg) and total dose of cisplatin. b. The linear relationship between actually utilized dose of cisplatin (mg) and volume of the perfusate retained in the HIPEC treatment system (ml). c. The linear relationship between the observed value of actually utilized dose of cisplatin (mg) and the predicted value of actually utilized dose of cisplatin (mg). AD, actually utilized dose (mg); HIPEC, hyperthermic intraperitoneal chemotherapy; TD, total dose (mg); VPretained, volume of the perfusate that was retained in the treatment system at the end of hyperthermic intraperitoneal chemotherapy (ml)
HIPEC-related AEs are summarized in supplementary Table 1. Following HIPEC, the most common AE was abdominal pain/distention, which was noted in ten patients (16.1%). Four patients (6.5%) reported AEs of grade 3, including 2 cases of neutropenia, one case of abdominal pain, and one case of vomiting. No patient developed AEs of grade 4.
Within a median follow-up time of 23 months (range: 9–35 months), recurrence was noted in 35 patients (56.4%), and the median recurrence-free survival (PFS) time was 16 months (range: 4–29 months). Ten patients (16.1%) died of disease, and the median overall survival (OS) time was not reached. In Cox regression analysis, we did not find that AD was associated with PFS [hazard ratio (HR) = 1.02, 95% confidence interval (CI): 0.98–1.06; P = 0.428] or OS (HR = 1.01, 95% CI: 0.95–1.07; P = 0.813).
Discussion
HIPEC has evolved over three decades and cisplatin is among the first-line drugs. However, there is no clearly defined standardization of regimen for cisplatin in the hyperthermic setting, and the reported dose in previous studies varies significantly, from 15 mg/m2 to 250 mg/m2 [13, 18, 19]. The most accepted cisplatin based HIPEC regimens in literature are the “Sugarbaker Regimen” [add cisplatin (50 mg/m2) + doxorubicin (15 mg/m2) to 2 L 1.5% dextrose peritoneal dialysis solution; treatment duration: 90 min] [20] and the “National Cancer Institute Milan Regimen” [15.25 mg/L of doxorubicin and 43 mg/L of cisplatin for 90-min HIPEC treatment; chemotherapy solution 4–6 L based on capacity of the peritoneal space] [13, 21]. Despite of this, neither of them has been recommended in current guidelines or validated in gynecologic cancer patients. Most of the side effects associated with hyperthermic cisplatin are dose dependent [22], so the lack of a standard dose regimen represents a notable challenge for the safe application of HIPEC. During HIPEC, the TD of cisplatin can be divided into two portions: one portion (AD) is directly absorbed or retained in the peritoneal cavity, while the other portion (LD) is retained in the perfusate and exits the body at the end of treatment. The variable AD is critical since it enables physicians to know the uptake quantity of cisplatin and thus can be used to tailor dose regimens. In the present study, we found that the AD is significantly correlated with the TD and VPretained. Based on these two factors, an equation was established with an adjusted R2 = 0.698, which suggested a moderate ability to predict the AD. In addition, we did not find that AD had prognostic impact.
The pharmacokinetics of cisplatin under hyperthermic conditions have been investigated previously [14–16]. Cashin’s study included ten patients who received HIPEC for peritoneal surface malignancies [14]. A combination of cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) was added to the perfusate, which was administered at 41.1–43 °C for a duration of 90 min. The reported mean half-life (t1/2) of perfusate cisplatin was 18.4 min. Accordingly, the authors concluded that after 75 min, there is little active cisplatin left in the perfusate. In another study by Ansaloni et al., 13 ovarian cancer patients received HIPEC, and a combination of cisplatin (100 mg/m2) and paclitaxel (175 mg/m2) was given at 41–43 °C [15]. Similarly, the authors reported that both drugs could be rapidly taken up from the perfusate by peritoneal tissue and the absorption of cisplatin could not be influenced by lowering the time of perfusion to 60 min. The present study is retrospective, so it is impossible for us to get patients’ blood sample and carry out pharmacokinetic assessment. Given the importance of the amount of cisplatin actually utilized in the living body, we calculated the utility rate of cisplatin using AD/TD ratio, which could be considered an indirect pharmacokinetic parameter. The median cisplatin utility rate in our cohort was 79.2% (range: 62.2–90.4%); therefore, approximately 80% of cisplatin was utilized after 60 min of HIPEC. This result indicates efficient uptake of cisplatin during HIPEC, which is consistent with previous reports [14, 15]. Loss of cisplatin during HIPEC is inevitable. Given our findings and current evidence, the necessity of minimizing the loss by methods such as flushing the device at the end of HIPEC is worth investigation in future studies.
In the NCCN ovarian cancer guidelines, the recommended dose for hyperthermic cisplatin is 100 mg/m2 [9]. This recommendation is based on the phase III OVHIPEC trial [4], where 245 patients were randomized to receive IDS either with or without HIPEC. The authors reported that the addition of HIPEC did not increase the risk of AEs. However, the administration of cisplatin in this trial was according to the following schedule: 50% of the dose at start, 25% at 30 min and 25% at 60 min. In this way, the maximum dose in the abdomen was lower than 100 mg/m2. An additional concern is that information on the influence of HIPEC on renal function was not detailed. Therefore, it remains unknown whether a dose of 100 mg/m2 of cisplatin is safe for HIPEC. In the present study, all patients received a dose of 70 mg/m2 cisplatin. The rationality of this dose regimen has been validated in Gouy’s study [23]. In the phase I dose escalation trial, four dose levels were planned for cisplatin: 50, 60, 70, and 80 mg/m2. The observed grade 4 dose-limiting toxicity was renal insufficiency, which did not occur until cisplatin was administered at dose level 4 (80 mg/m2). Because several patients developed prolonged renal function impairment, the authors recommended a 70 mg/m2 dose of cisplatin for HIPEC. In the current cohort, no patients developed kidney dysfunction following HIPEC, which is in line with our previous findings and confirms Gouy’s conclusion [23].
HIPEC-related kidney injury has been a clinical concern. The reported incidence of major renal toxicity ranges from 1.3 to 5.7% [24–26]. Among previous studies regarding this issue, Cata’s study, which retrospectively reviewed 475 patients, has the largest sample size examined to date [27]. The authors reported that acute kidney injury (AKI) following HIPEC was independently associated with patient age, body mass index, the use of cisplatin or oxaliplatin as the agent, the preoperative administration of pregabalin and estimated blood loss [27]. In addition, the risk of kidney dysfunction is also characterized by ethnical differences [28]. For Chinese ovarian cancer patients, Sin et al. identified predictors for AKI following HIPEC that included age, baseline levels of creatinine, the estimated glomerular filtration rate and albumin, the number of cycles of preoperative carboplatin, the time interval between NACT and debulking surgery, and the volume of blood transfusions [29]. Of note, Sin et al. reported that 9.4% of their patients developed NCI-CTCAE grade 3 and 4 renal impairment, and 5.7% of their patients needed renal replacement therapy [29]. The incidence reported in this study is much higher than that reported in other studies [24–26], and a possible explanation is that many patients received cycles of platinum-based chemotherapy before HIPEC, and a high dose of cisplatin (90 mg/m2) was prescribed in HIPEC. Although an even higher dose of cisplatin (100 mg/m2) was used in OVHIPEC trial, some aspects of the trial are questionable, which has been discussed above. Besides, all patients in this trial received sodium thiosulphate and adequate hydration. Appropriate use of these measures can effectively prevent nephrotoxicity which could also provide additional explanation for why such high dose of hyperthermic cisplatin did not result in an increased incidence of kidney injury [30]. Collectively, current evidence suggests that HIPEC-related nephrotoxicity is complex and can be affected by many factors. The selection of patients based on risk stratification, optimized cisplatin dose regimens and appropriate protective measures can help reduce the risk of HIPEC-related nephrotoxicity.
The treatment temperature in our study was 43 ± 0.01 °C, which is in accordance with the CACA guidelines [10]. This recommendation is based on the evidence that the synergistic effect of hyperthermia and cisplatin can be dramatically increased at 42 °C [10]. Data from clinical research also confirmed the safety and effectiveness of HIPEC at 43 °C [31–34]. In general, the properties of biological tissues, the toxicity of drugs and their mutual influences change under hyperthermic conditions; some of the changes are temperature dependent [35]. Therefore, it is necessary to explore drug uptake in the hyperthermic setting at a given temperature. In addition, other parameters, including flow rate during HIPEC and perfusate dwelling time, have potential impact on cisplatin uptake. However, these data were not available in the present study; their influence is worthy of further studies.
The present study provides the first tool that can be used to calculate the AD of cisplatin during HIPEC, which makes it possible to further explore and determine whether a supplementation on cisplatin is necessary in the clinical setting. Of note, AD can be influenced by many factors. However, since the design of present study is retrospective, the omission of potential factors is inevitable, which certainly adversely affects the accuracy of the predictive equation. In addition, the adjusted R2 value of the predictive equation was 0.698 indicating that predictive performance has not yet reached a satisfying level. Given these limitations, we must acknowledge that the prediction formula still needs to be refined and more trials are needed to validate its performance. In addition, HIPEC is recommended as an adjuvant therapy following cytoreduction in the CACA guidelines [10]; however, since all patients in the present study were retrospectively reviewed, we cannot reasonably explain how patients were selected to receive cytoreduction plus HIPEC rather than cytoreduction alone. Another limitation is that not all patients received the same comprehensive treatment model, and the follow-up period was short. Therefore, although the recurrence-free survival of our cohort is comparable to that in previous studies, the median OS was not achieved. Additionally, the sample size of the present study was relatively small, and the potential influence from the type of HIPEC device cannot be excluded.
Conclusions
For ovarian cancer patients who receive cisplatin for HIPEC at 43 °C, the AD of cisplatin can be calculated from the TD and VPretained using the following equation: AD (mg) = 30.079 + 0.667 TD (mg) – 0.010 VPretained (ml). AD has no prognostic influence. Our work could help guide dose planning for cisplatin when HIPEC is indicated. Larger prospective trials are needed to validate our findings.
Supplementary Information
Additional file 1. Adverse events.
Abbreviations
ADActually utilized dose
AKIAcute kidney injury
AEAdverse event
BMIBody mass index
CIConfidence interval
HRHazard ratio
HIPECHyperthermic intraperitoneal chemotherapy
ICP-MSInductively coupled plasma mass spectrometry
IDSInterval debulking surgery
IPCIntraperitoneal chemotherapy
LDLosing dose
NCCNNational Comprehensive Cancer Network
NACTNeoadjuvant chemotherapy
OSOverall survival
PDSPrimary debulking surgery
PFSRecurrence-free survival
CACAThe China Anti-Cancer Association
NCI-CTCAEThe National Cancer Institute Common Terminology Criteria for Adverse Events
TDTotal dose
VpretainedVolume of the perfusate that was retained
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Wu-yun Wang and Miao-fang Wu contributed equally to this work.
We would like to acknowledge all the research coordinators at the Department of Gynecologic Oncology at Sun Yat-sen Memorial Hospital. We are deeply grateful to the patients who provided samples for this study and all clinicians who referred cases.
Authors’ contributions
Conceptualization, ZQL, JL; methodology, JL; software, HL; formal analysis, WYW; data curation, WYW, HL; writing-original draft preparation, WYW, JL; writing-review and editing, JL, ZQL; supervision, ZQL, JL; project administration, WYW, MFW, DBW, LJW; funding acquisition, JL. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by China Scholarship Council, grant number 201906385061.
Availability of data and materials
The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of the Sun Yat-sen Memorial Hospital (Approval No. SYSEC-KY-KS-2020-046) in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
Consent for publication
The publication has been approved by all co-authors.
Competing interests
None of the authors declared any conflict of interest regarding the subject of the study. | CISPLATIN | DrugsGivenReaction | CC BY | 33419462 | 18,778,172 | 2021-01-08 |
What was the dosage of drug 'CISPLATIN'? | Calculating the dose of cisplatin that is actually utilized in hyperthermic intraperitoneal chemotherapy among ovarian cancer patients.
BACKGROUND
Hyperthermic intraperitoneal chemotherapy (HIPEC) is an important treatment for ovarian cancer. A certain portion of cisplatin exits the body via the perfusate at the end of HIPEC, so full-dose utilization cannot be achieved. Herein, we sought to explore how much cisplatin is actually utilized and its prognostic influence.
METHODS
Cisplatin (70 mg/m2) was given at 43 °C for 90 min. The actually utilized dose (AD) of cisplatin was calculated using the following formula: AD (mg) = total dose (TD) (mg)-losing dose (LD) (mg); LD = volume (ml) of the perfusate (VPretained) that was retained in the HIPEC treatment system at the end of HIPEC * concentration of cisplatin in the perfusate (mg/ml).
RESULTS
Sixty-two ovarian cancer patients were included. The median TD, median LD and median AD were 95 mg, 20.7 mg and 75.8 mg, respectively. The utility rate of cisplatin (AD/TD ratio) was 79.2%. On simple linear regression analysis, the TD and VPretained were found to significantly predict the AD. Based on these two factors, multiple linear regression analysis was conducted, and a significant regression equation was formulated [F (2, 59) = 71.419, P < 0.0001]: predicted AD (mg) = 30.079 + 0.667 TD (mg) - 0.010 VPretained (ml) (adjusted R2 = 0.698). In Cox regression analysis, AD was not noted to be associated with progression free survival or overall survival.
CONCLUSIONS
For ovarian cancer patients who receive cisplatin for HIPEC at 43 °C, the AD of cisplatin can be predicted using a regression equation and it has no prognostic impact.
Introduction
Ovarian cancer is the deadliest gynecologic cancer and is usually diagnosed after the cancer has spread beyond the ovary [1]. Primary debulking surgery (PDS) combined with chemotherapy has been the first-line treatment for ovarian cancer patients. However, even among patients without evidence of disease following treatment, 70% experience recurrence within the subsequent 3 years, and almost 80% succumb to their disease [2].
Because of a clear tendency to develop peritoneal metastasis, attempts to improve outcomes for this patient population have prompted the investigation of intraperitoneal chemotherapy (IPC), and its effect has been validated [3]. IPC can also be delivered under hyperthermic conditions, which is termed hyperthermic intraperitoneal chemotherapy (HIPEC). An increasing number of studies have shown a survival benefit associated with HIPEC among ovarian cancer patients [4–8]. Based on this evidence, HIPEC has been recommended in the National Comprehensive Cancer Network (NCCN) guidelines for patients receiving interval debulking surgery (IDS) [9]. In the China Anti-Cancer Association (CACA) guidelines, HIPEC is recommended as an adjuvant treatment for gynecologic cancer patients with peritoneal carcinomatosis; currently, it has been a publicly approved therapy in China and its costs are covered by insurance plans [10].
Owing to a favorable peritoneal plasma gradient, cisplatin is the preferred agent for IPC [11]. The addition of hyperthermia to intraperitoneal cisplatin can result in synergistic effects, thereby enhancing cytotoxicity [12]. Therefore, cisplatin is also the most commonly used drug in HIPEC [13]. A noteworthy observation in clinical practice is that a certain portion of cisplatin exits the body via the perfusate at the end of treatment, so full cisplatin uptake cannot be achieved. Previous investigations have explored the pharmacokinetic features of cisplatin in HIPEC [14–16]. However, no investigator could provide a clear-cut answer to the following critical question: how much cisplatin is actually utilized by a patient during HIPEC? Accordingly, it is unclear whether the amount of cisplatin depletion adversely affects therapeutic effect. We herein conducted a study to predict the actual uptake dose of cisplatin based on clinical variables that are easy to obtain and investigate its prognostic effect. From a clinical perspective, we believe that our findings are conducive to optimizing the dose planning and schedule of cisplatin in HIPEC.
Materials and methods
After Institutional Review Board approval was obtained (Approval No. SYSEC-KY-KS-2020-046), a retrospective chart review was conducted. Ovarian cancer patients who received cisplatin for HIPEC between 2016 and 2018 were identified. Patients who were considered for HIPEC underwent detailed counseling with regard to the potential risks and benefits within the context of previously published clinical trials and guidelines. All patients provided signed informed consent. Data from patients who received intravenous platinum within 2 weeks before HIPEC and patients who did not undergo the complete HIPEC procedure were excluded.
Surgical complexity of the debulking surgery was based on a complexity score which was calculated using a published scoring system [17]. At the end of cytoreduction, four tubes were placed (two in the bilateral subdiaphragmatic space for use as inlet tubes and two in the pelvic cavity for use as an outlet tubes) before closing the incision, which were used to administrate HIPEC. HIPEC was given following surgery using a close technique. A high-precision hyperthermic intraperitoneal perfusion treatment system with a precision of ±0.10 °C for temperature control and ± 5% for flow control (approved by the State Food Drug Administration of China, approval no. 2009–3,260,924) was utilized. Cisplatin was given at a dose of 70 mg per square meter and was added to 3000–5000 ml of saline solution. The perfusate was heated and circulated at a flow rate of 300–500 ml/min. The perfusion velocity was adjusted to ensure that the entire abdomen was exposed to the perfusate (the initial velocity was 300 ml/min and increased gradually until the patient felt floated or until a flow rate of 500 ml/min was achieved). An intraabdominal temperature of 43 °C was maintained and measured by the treatment system using temperature monitoring probes in the infusion and outflow catheters. The HIPEC procedure took 90 min in total, consisting of a 30 min preheating period and a 60 min perfusion period. All patients received continuous intravenous fluids to assure adequate hydration. During the treatment, vital signs and urine output were monitored continually. After HIPEC treatment, the perfusate retained in the treatment system and in the tubes was collected after removing the tubes, and then the volume was measured. Thereafter, a portion of the perfusate was stored at − 80 °C and analyzed within 3 weeks. Perfusate collecting and volume assessment have been integrated into routine clinical care in our institution since 2015. Cisplatin concentrations in the perfusate were measured by inductively coupled plasma mass spectrometry (ICP-MS; PerkinElmer, America). The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0 was used to grade HIPEC-related adverse events (AEs) that presented within 3 weeks of HIPEC.
The Kolmogorov-Smirnov test was used to determine the distribution of continuous variables. Student’s t test was used to compare normally distributed continuous variables, whereas the Mann-Whitney U test was used to compare nonnormally distributed variables. The following equation was applied to calculate the quantity of cisplatin uptake during HIPEC:
Actually utilized doseADmg=total doseTDmg−losing doseLDmg TD=70mg/m2∗body surface aream2the resultingTDwas rounded to the closest integer LD=volumemlof the perfusateVPretainedthat was retained in the treatment systemattheendof HIPEC∗concentration of cisplatin in the perfusatemg/ml.
To explore associations between the AD and potential clinical variables, linear regression analysis was conducted. These variables included patient age, body mass index (BMI), TD, VPretained and serum levels of creatinine and albumin prior to HIPEC. Assumptions that underpin linear regression were confirmed as described previously. The final regression equation was established using a multiple linear regression model with the enter method. Variables with P values < 0.05 in the simple linear regression analysis were entered into the multiple linear regression analysis. Cox proportional hazards regression model was used to explore the prognostic influence of AD. Statistical tests were two-sided, and a P value < 0.05 was considered statistically significant. All data analyses were performed with SPSS 20.0 for Windows (SPSS, Inc., Chicago, IL).
Results
A total of 62 patients were included in the final analysis. Table 1 summarizes the patient demographics and clinical characteristics. Because of massive ascites and pleural effusion, six patients had restricted activity (9.7%). Before HIPEC, abnormal serum creatinine levels were noted in one patient (1.6%) who had an elevated serum creatinine level (137 μmol/l) since diagnosis. This patient had no complaints and denied a history of kidney disease. Repeated creatinine tests and further kidney function evaluations were performed, but no evidence of acute or chronic kidney injury was identified. Then, the mean serum creatinine value (159 μmol/l) was used for the analysis. Of our cohort, 44 patients (71.0%) received HIPEC following PDS, while 18 patients (29.0%) received HIPEC following IDS.
Table 1 Demographic and clinical characteristics of patients
Characteristic
Age (years), median (range) 51 (18, 76)
BMI (kg/m2), median (range) 22.1 (15.8, 34.8)
Body surface area (m2), median (range) 1.42 (1.21, 1.71)
ECOG performance status (%)
Normal activity 56 (90.3)
Restricted activity 6 (9.7)
Histology (%)
High grade serous adenocarcinoma 46 (74.2)
Mucinous adenocarcinoma 3 (4.8)
High grade endometrioid adenocarcinoma 3 (4.8)
Clear cell carcinoma 5 (8.1)
Malignant mixed mullerian tumor 5 (8.1)
FIGO stage (%)
IIIC 43 (69.4)
IV 19 (30.7)
Surgical treatment (%)
Primary debulking surgery 44 (71.0)
Interval debulking surgery 18 (29.0)
Gross residual disease (%)
Yes 43 (69.4)
No 19 (30.7)
Surgical complexity (%)
Low 5 (8.1)
Moderate 40 (64.5)
High 17 (27.4)
ICU stay (%)
Yes 2 (3.2)
No 60 (96.8)
Serum creatinine (umol/L), median (range)
Prior to HIPEC 63.5 (49, 159)
Following HIPEC 62.0 (48, 149)
Serum albumin (g/l), median (range)
Prior to HIPEC 25 (15, 36)
Following HIPEC 22 (15, 30)
BMI Body mass index, ECOG Eastern cooperative oncology group, HIPEC Hyperthermic intraperitoneal chemotherapy, ICU Intensive care unit
Table 2 shows variables that were related to the cisplatin dose. The median TD and LD values were 95 mg (range: 85–120 mg) and 20.7 mg (range: 9.6–37.8 mg), respectively. Based on the formulation mentioned above, the median calculated AD value was 75.8 mg (range: 48.3–92.4 mg). The AD/TD ratio refers to the utility rate of cisplatin, and the median percentage was 79.2% (range: 62.2–90.4%).
Table 2 Hyperthermic intraperitoneal chemotherapy related parameters
Parameter
TD (mg), median (range) 95 (85, 120)
Perfusate at the end of HIPEC
Volume (ml), median (range) 1835 (1050, 2670)
Concentration of cisplatin (μg/ml), median (range) 11.3 (6.6, 19.4)
LD (mg), median (range) 20.7 (9.6, 37.8)
AD (mg), median (range) 75.8 (48.3, 92.4)
Utility rate of cisplatina (%), median (range) 79.2 (62.2, 90.4)
AD Actually utilized dose, LD Losing dose, HIPEC Hyperthermic intraperitoneal chemotherapy, TD Total dose;
aUtility rate of cisplatin = actually used dose of cisplatin (mg)/ total dose of cisplatin (mg)
The results of the linear regression analysis are summarized in Table 3. The TD and VPretained had a linear relationship with the AD (Fig. 1a and b) and were able to significantly predict the AD on simple linear regression analysis. Based on these two factors, multiple linear regression analysis was conducted, and a significant regression equation was formulated [F (2, 59) = 71.419, P < 0.0001], with an R2 of 0.708. The formula was as follows: predicted AD (mg) = 30.079 + 0.667 TD (mg) – 0.010 VPretained (ml). Therefore, when maintaining all other variables constant, the AD increased 0.667 mg for each milligram increase in the TD, while the AD decreased 0.010 mg for each milliliter increase in the VPretained. Both the TD and VPretained were significant predictors for the AD. The TD and VPretained accounted for 69.8% (adjusted R2 = 0.698) of the explained variability in the AD. Figure 1c illustrates scatter plots of the actual vs predicted AD values.
Table 3 Linear regression model results for actually utilized dose of cisplatin
β 95% CI for β P value β 95% CI for β P value
Age (years) −0.012 −0.169, 0.146 0.881 – – –
BMI (kg/m2) −0.117 −0.705, 0.472 0.693 – – –
Serum creatinine prior to HIPEC (umol/l) 0.013 −0.103, 0.129 0.822 – – –
Serum albumin (g/l) prior to HIPEC 0.078 −0.308, 0.464 0.689 – – –
TD (mg) 0.777 0.554, 1.000 < 0.001 0.667 0.500, 0.833 < 0.001
VPretained (ml) −0.012 −0.016, − 0.008 < 0.001 0.010 −0.013, − 0.007 < 0.001
BMI Body mass index, HIPEC Hyperthermic intraperitoneal chemotherapy, TD Total dose, VPretained Volume (ml) of the perfusate that was retained in the treatment system at the end of hyperthermic intraperitoneal chemotherapy;
Fig. 1 a. The linear relationship between actually utilized dose of cisplatin (mg) and total dose of cisplatin. b. The linear relationship between actually utilized dose of cisplatin (mg) and volume of the perfusate retained in the HIPEC treatment system (ml). c. The linear relationship between the observed value of actually utilized dose of cisplatin (mg) and the predicted value of actually utilized dose of cisplatin (mg). AD, actually utilized dose (mg); HIPEC, hyperthermic intraperitoneal chemotherapy; TD, total dose (mg); VPretained, volume of the perfusate that was retained in the treatment system at the end of hyperthermic intraperitoneal chemotherapy (ml)
HIPEC-related AEs are summarized in supplementary Table 1. Following HIPEC, the most common AE was abdominal pain/distention, which was noted in ten patients (16.1%). Four patients (6.5%) reported AEs of grade 3, including 2 cases of neutropenia, one case of abdominal pain, and one case of vomiting. No patient developed AEs of grade 4.
Within a median follow-up time of 23 months (range: 9–35 months), recurrence was noted in 35 patients (56.4%), and the median recurrence-free survival (PFS) time was 16 months (range: 4–29 months). Ten patients (16.1%) died of disease, and the median overall survival (OS) time was not reached. In Cox regression analysis, we did not find that AD was associated with PFS [hazard ratio (HR) = 1.02, 95% confidence interval (CI): 0.98–1.06; P = 0.428] or OS (HR = 1.01, 95% CI: 0.95–1.07; P = 0.813).
Discussion
HIPEC has evolved over three decades and cisplatin is among the first-line drugs. However, there is no clearly defined standardization of regimen for cisplatin in the hyperthermic setting, and the reported dose in previous studies varies significantly, from 15 mg/m2 to 250 mg/m2 [13, 18, 19]. The most accepted cisplatin based HIPEC regimens in literature are the “Sugarbaker Regimen” [add cisplatin (50 mg/m2) + doxorubicin (15 mg/m2) to 2 L 1.5% dextrose peritoneal dialysis solution; treatment duration: 90 min] [20] and the “National Cancer Institute Milan Regimen” [15.25 mg/L of doxorubicin and 43 mg/L of cisplatin for 90-min HIPEC treatment; chemotherapy solution 4–6 L based on capacity of the peritoneal space] [13, 21]. Despite of this, neither of them has been recommended in current guidelines or validated in gynecologic cancer patients. Most of the side effects associated with hyperthermic cisplatin are dose dependent [22], so the lack of a standard dose regimen represents a notable challenge for the safe application of HIPEC. During HIPEC, the TD of cisplatin can be divided into two portions: one portion (AD) is directly absorbed or retained in the peritoneal cavity, while the other portion (LD) is retained in the perfusate and exits the body at the end of treatment. The variable AD is critical since it enables physicians to know the uptake quantity of cisplatin and thus can be used to tailor dose regimens. In the present study, we found that the AD is significantly correlated with the TD and VPretained. Based on these two factors, an equation was established with an adjusted R2 = 0.698, which suggested a moderate ability to predict the AD. In addition, we did not find that AD had prognostic impact.
The pharmacokinetics of cisplatin under hyperthermic conditions have been investigated previously [14–16]. Cashin’s study included ten patients who received HIPEC for peritoneal surface malignancies [14]. A combination of cisplatin (50 mg/m2) and doxorubicin (15 mg/m2) was added to the perfusate, which was administered at 41.1–43 °C for a duration of 90 min. The reported mean half-life (t1/2) of perfusate cisplatin was 18.4 min. Accordingly, the authors concluded that after 75 min, there is little active cisplatin left in the perfusate. In another study by Ansaloni et al., 13 ovarian cancer patients received HIPEC, and a combination of cisplatin (100 mg/m2) and paclitaxel (175 mg/m2) was given at 41–43 °C [15]. Similarly, the authors reported that both drugs could be rapidly taken up from the perfusate by peritoneal tissue and the absorption of cisplatin could not be influenced by lowering the time of perfusion to 60 min. The present study is retrospective, so it is impossible for us to get patients’ blood sample and carry out pharmacokinetic assessment. Given the importance of the amount of cisplatin actually utilized in the living body, we calculated the utility rate of cisplatin using AD/TD ratio, which could be considered an indirect pharmacokinetic parameter. The median cisplatin utility rate in our cohort was 79.2% (range: 62.2–90.4%); therefore, approximately 80% of cisplatin was utilized after 60 min of HIPEC. This result indicates efficient uptake of cisplatin during HIPEC, which is consistent with previous reports [14, 15]. Loss of cisplatin during HIPEC is inevitable. Given our findings and current evidence, the necessity of minimizing the loss by methods such as flushing the device at the end of HIPEC is worth investigation in future studies.
In the NCCN ovarian cancer guidelines, the recommended dose for hyperthermic cisplatin is 100 mg/m2 [9]. This recommendation is based on the phase III OVHIPEC trial [4], where 245 patients were randomized to receive IDS either with or without HIPEC. The authors reported that the addition of HIPEC did not increase the risk of AEs. However, the administration of cisplatin in this trial was according to the following schedule: 50% of the dose at start, 25% at 30 min and 25% at 60 min. In this way, the maximum dose in the abdomen was lower than 100 mg/m2. An additional concern is that information on the influence of HIPEC on renal function was not detailed. Therefore, it remains unknown whether a dose of 100 mg/m2 of cisplatin is safe for HIPEC. In the present study, all patients received a dose of 70 mg/m2 cisplatin. The rationality of this dose regimen has been validated in Gouy’s study [23]. In the phase I dose escalation trial, four dose levels were planned for cisplatin: 50, 60, 70, and 80 mg/m2. The observed grade 4 dose-limiting toxicity was renal insufficiency, which did not occur until cisplatin was administered at dose level 4 (80 mg/m2). Because several patients developed prolonged renal function impairment, the authors recommended a 70 mg/m2 dose of cisplatin for HIPEC. In the current cohort, no patients developed kidney dysfunction following HIPEC, which is in line with our previous findings and confirms Gouy’s conclusion [23].
HIPEC-related kidney injury has been a clinical concern. The reported incidence of major renal toxicity ranges from 1.3 to 5.7% [24–26]. Among previous studies regarding this issue, Cata’s study, which retrospectively reviewed 475 patients, has the largest sample size examined to date [27]. The authors reported that acute kidney injury (AKI) following HIPEC was independently associated with patient age, body mass index, the use of cisplatin or oxaliplatin as the agent, the preoperative administration of pregabalin and estimated blood loss [27]. In addition, the risk of kidney dysfunction is also characterized by ethnical differences [28]. For Chinese ovarian cancer patients, Sin et al. identified predictors for AKI following HIPEC that included age, baseline levels of creatinine, the estimated glomerular filtration rate and albumin, the number of cycles of preoperative carboplatin, the time interval between NACT and debulking surgery, and the volume of blood transfusions [29]. Of note, Sin et al. reported that 9.4% of their patients developed NCI-CTCAE grade 3 and 4 renal impairment, and 5.7% of their patients needed renal replacement therapy [29]. The incidence reported in this study is much higher than that reported in other studies [24–26], and a possible explanation is that many patients received cycles of platinum-based chemotherapy before HIPEC, and a high dose of cisplatin (90 mg/m2) was prescribed in HIPEC. Although an even higher dose of cisplatin (100 mg/m2) was used in OVHIPEC trial, some aspects of the trial are questionable, which has been discussed above. Besides, all patients in this trial received sodium thiosulphate and adequate hydration. Appropriate use of these measures can effectively prevent nephrotoxicity which could also provide additional explanation for why such high dose of hyperthermic cisplatin did not result in an increased incidence of kidney injury [30]. Collectively, current evidence suggests that HIPEC-related nephrotoxicity is complex and can be affected by many factors. The selection of patients based on risk stratification, optimized cisplatin dose regimens and appropriate protective measures can help reduce the risk of HIPEC-related nephrotoxicity.
The treatment temperature in our study was 43 ± 0.01 °C, which is in accordance with the CACA guidelines [10]. This recommendation is based on the evidence that the synergistic effect of hyperthermia and cisplatin can be dramatically increased at 42 °C [10]. Data from clinical research also confirmed the safety and effectiveness of HIPEC at 43 °C [31–34]. In general, the properties of biological tissues, the toxicity of drugs and their mutual influences change under hyperthermic conditions; some of the changes are temperature dependent [35]. Therefore, it is necessary to explore drug uptake in the hyperthermic setting at a given temperature. In addition, other parameters, including flow rate during HIPEC and perfusate dwelling time, have potential impact on cisplatin uptake. However, these data were not available in the present study; their influence is worthy of further studies.
The present study provides the first tool that can be used to calculate the AD of cisplatin during HIPEC, which makes it possible to further explore and determine whether a supplementation on cisplatin is necessary in the clinical setting. Of note, AD can be influenced by many factors. However, since the design of present study is retrospective, the omission of potential factors is inevitable, which certainly adversely affects the accuracy of the predictive equation. In addition, the adjusted R2 value of the predictive equation was 0.698 indicating that predictive performance has not yet reached a satisfying level. Given these limitations, we must acknowledge that the prediction formula still needs to be refined and more trials are needed to validate its performance. In addition, HIPEC is recommended as an adjuvant therapy following cytoreduction in the CACA guidelines [10]; however, since all patients in the present study were retrospectively reviewed, we cannot reasonably explain how patients were selected to receive cytoreduction plus HIPEC rather than cytoreduction alone. Another limitation is that not all patients received the same comprehensive treatment model, and the follow-up period was short. Therefore, although the recurrence-free survival of our cohort is comparable to that in previous studies, the median OS was not achieved. Additionally, the sample size of the present study was relatively small, and the potential influence from the type of HIPEC device cannot be excluded.
Conclusions
For ovarian cancer patients who receive cisplatin for HIPEC at 43 °C, the AD of cisplatin can be calculated from the TD and VPretained using the following equation: AD (mg) = 30.079 + 0.667 TD (mg) – 0.010 VPretained (ml). AD has no prognostic influence. Our work could help guide dose planning for cisplatin when HIPEC is indicated. Larger prospective trials are needed to validate our findings.
Supplementary Information
Additional file 1. Adverse events.
Abbreviations
ADActually utilized dose
AKIAcute kidney injury
AEAdverse event
BMIBody mass index
CIConfidence interval
HRHazard ratio
HIPECHyperthermic intraperitoneal chemotherapy
ICP-MSInductively coupled plasma mass spectrometry
IDSInterval debulking surgery
IPCIntraperitoneal chemotherapy
LDLosing dose
NCCNNational Comprehensive Cancer Network
NACTNeoadjuvant chemotherapy
OSOverall survival
PDSPrimary debulking surgery
PFSRecurrence-free survival
CACAThe China Anti-Cancer Association
NCI-CTCAEThe National Cancer Institute Common Terminology Criteria for Adverse Events
TDTotal dose
VpretainedVolume of the perfusate that was retained
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Wu-yun Wang and Miao-fang Wu contributed equally to this work.
We would like to acknowledge all the research coordinators at the Department of Gynecologic Oncology at Sun Yat-sen Memorial Hospital. We are deeply grateful to the patients who provided samples for this study and all clinicians who referred cases.
Authors’ contributions
Conceptualization, ZQL, JL; methodology, JL; software, HL; formal analysis, WYW; data curation, WYW, HL; writing-original draft preparation, WYW, JL; writing-review and editing, JL, ZQL; supervision, ZQL, JL; project administration, WYW, MFW, DBW, LJW; funding acquisition, JL. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by China Scholarship Council, grant number 201906385061.
Availability of data and materials
The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of the Sun Yat-sen Memorial Hospital (Approval No. SYSEC-KY-KS-2020-046) in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
Consent for publication
The publication has been approved by all co-authors.
Competing interests
None of the authors declared any conflict of interest regarding the subject of the study. | 43 DEGREE C FOR 90 MIN | DrugDosageText | CC BY | 33419462 | 18,778,172 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ACETAMINOPHEN, ACETAMINOPHEN\CODEINE PHOSPHATE\DOXYLAMINE SUCCINATE, ALBUTEROL, ASPIRIN, CHOLECALCIFEROL, DENOSUMAB, DOCUSATE, DOXYLAMINE, DULOXETINE, FLUCLOXACILLIN, HYDROMORPHONE, HYDROXOCOBALAMIN, PANTOPRAZOLE, POLYETHYLENE GLYCOLS, PREDNISOLONE, TOPIRAMATE | DrugsGivenReaction | CC BY-NC | 33419747 | 18,849,246 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ACETAMINOPHEN\HYDROCODONE, FLUCLOXACILLIN, GENTAMICIN | DrugsGivenReaction | CC BY-NC | 33419747 | 15,450,932 | 2021-01-08 |
What was the administration route of drug 'FLUCLOXACILLIN'? | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33419747 | 18,962,864 | 2021-01-08 |
What was the dosage of drug 'ACETAMINOPHEN\HYDROCODONE'? | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | UNKNOWN | DrugDosageText | CC BY-NC | 33419747 | 15,450,932 | 2021-01-08 |
What was the dosage of drug 'GENTAMICIN'? | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | UNKNOWN | DrugDosageText | CC BY-NC | 33419747 | 15,450,932 | 2021-01-08 |
What was the outcome of reaction 'Acute kidney injury'? | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33419747 | 18,849,246 | 2021-01-08 |
What was the outcome of reaction 'Metabolic acidosis'? | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33419747 | 18,849,246 | 2021-01-08 |
What was the outcome of reaction 'Pyroglutamic acidosis'? | Flucloxacillin and paracetamol induced pyroglutamic acidosis.
A 75-year-old woman was admitted to a regional hospital with an acute kidney injury (AKI) and nausea on a background of recent treatment for Staphylococcus aureus bacteraemia secondary to pneumonia. The treatment thereof resulted in a high anion gap metabolic acidosis (HAGMA). The pneumonia was initially treated with intravenous piperacillin and tazobactam and the patient transferred to a tertiary hospital. There, the diagnosis of S. aureus bacteraemia secondary to a pulmonary source was confirmed and treatment was changed to intravenous flucloxacillin and the patient was discharged to hospital in the home (HITH is a service that allows short-term healthcare at home to be provided to people who would otherwise need to be in hospital) to complete the antibiotic course. Five weeks after commencing flucloxacillin, the patient was referred back to hospital with nausea and worsening kidney function with an associated significant HAGMA. The patient has a background of chronic kidney disease and chronic back pain for which she was taking long-term paracetamol. The HAGMA was determined to be due to a pyroglutamic acidosis (PGA), deemed secondary to the combined use of paracetamol and flucloxacillin. This was subsequently confirmed with a plasma pyroglutamic acid concentration level of 7467 µmol/L (reference range 20-50 µmol/L) and a urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). To our knowledge, this is the highest plasma and urinary levels published to date. Furthermore, considering the common use of paracetamol and penicillins, it is important to recognise HAGMA as a potential complication of co-administration of paracetamol and iso-oxylopenicillin. The HAGMA resolved after cessation of flucloxacillin despite the continuation of paracetamol and without administration of N-acetylcysteine. PGA-related HAGMA appears to be a unique potential side effect of iso-oxylopenicillin rather than other beta-lactams.
Background
A high anion gap metabolic acidosis (HAGMA) is a common acid–base derangement resulting from a variety of metabolic changes. The majority of causes are summarised by the acronym GOLD MARK (Glycols, oxoproline, Lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis).1
A rarely identified cause of HAGMA is the accumulation of pyroglutamic acid (5-oxoproline), possibly due to being under-recognised and under-reported rather than reflecting a true rare prevalence.2–6 Pyroglutamic acidosis (PGA) can either be congenital or acquired.7 Congenital aetiology involves inborn errors of metabolism that specifically affect enzymes in the γ-glutamyl cycle, such as glutathione synthetase deficiency (refer to figure 1). In addition, PGA can be acquired in the setting of reduced glutathione or reduced cysteine states and as an adverse drug reaction (eg, flucloxacillin, paracetamol). The association of flucloxacillin and paracetamol with HAGMA was first noted in 1989 in a woman with haemolytic anaemia and neurological symptoms.8
Figure 1 γ-Glutamyl cycle.
The causes of and contributors to HAGMA can be difficult to accurately identify in patients who have multiple comorbidities and especially in the context of polypharmacy. PGA is usually a diagnosis of exclusion supported by the appropriate clinical scenario combined with plasma and/or urine pyroglutamic acid levels. Patients with comorbidities may be prescribed paracetamol and penicillins (isoxazolyl) often concurrently, and it is important to recognise that acquired PGA is likely to be under-reported and have significant sequelae in patients’ clinical course.9
Left unresolved, unmanaged metabolic acidosis can contribute significantly to mortality.2 The consequences of chronic HAGMA in patients with chronic kidney disease may include osteopenia, increased muscle catabolism, secondary hyperparathyroidism, reduced respiratory reserve and increased severity of subsequent infections.10 Therefore, it is important to manage and treat the underlying cause of HAGMA. There is limited literature on the accumulation of pyroglutamic acid resulting in HAGMA, and we report this case to alert clinicians of the need to consider PGA in the differential diagnosis of HAGMA.
Case presentation
A 75-year-old female presented to the emergency department with dyspnoea. She had been treated for recurrent lower respiratory tract infections by the general practitioner (GP) with oral antibiotics (12 cases in the past 14 months). Her relevant medical history included chronic kidney disease stage 3 (baseline creatinine 80–110 µmol/L), polymyalgia rheumatica requiring long-term steroids, asthma and chronic back pain. The pneumonia diagnosis was confirmed by a chest radiograph and CT showing multifocal nodular consolidation in the right lower lobe with cavitations and blood cultures were taken that grew Staphylococcus aureus.
Her medical history otherwise included depression, hypercholesterolaemia, gastro-oesophageal reflux disease, spondylosis, glaucoma, hypertension, lacunar stroke, transient ischaemic attack, vitamin B12 deficiency and vascular dementia.
Her long-term treatment included hydromorphone, paracetamol, topiramate, paracetamol–codeine–doxylamine, doxylamine, colecalciferol, aspirin, duloxetine, pantoprazole, prednisolone, docusate, macrogol, hydroxocobalamin, salbutamol and denosumab.
On presentation, she was initially afebrile, heart rate of 95 bpm, respiratory rate of 25 breaths per minute and oxygen saturation of 96%. On examination, there were crackles on the right base, dual heart sounds with no murmurs and no peripheral stigmata of infective endocarditis. She was subsequently treated for pneumonia and urinary tract infection with intravenous piperacillin–tazobactam. The working diagnosis was S. aureus bacteraemia secondary to a pulmonary source.
The patient was transferred to the closest tertiary hospital as the eventual need for further investigations, including a trans-oesophageal echo, was anticipated in the context of S. aureus bacteraemia. The treatment of her bacteraemia was eventually changed to intravenous flucloxacillin (2 g four times daily) once sensitivities were confirmed. Flucloxacillin was planned to continue for a further 5 weeks via peripherally inserted central catheter (PICC) on an 8 g/24 hours infuser that was monitored via hospital in the home (HITH).
Four weeks into the HITH treatment, the patient developed nausea and was investigated with blood results that showed worsening renal function associated with HAGMA. She was subsequently referred back to the regional hospital. Her heart rate was 105 bpm, respiratory rate of 20 breaths per minute and O2 sat 98% on room air. At that point, HAGMA was attributed to an acute kidney injury (AKI). Following adequate fluid resuscitation, HAGMA and AKI persisted. She was investigated for the AKI with a renal ultrasound which was negative and there were no eosinophils found in the urine. Interstitial nephritis secondary to flucloxacillin use was considered as another reason for her AKI but was deemed unlikely. The treatment plan was to commence sodium bicarbonate 840 mg once daily following consultation with the renal team. Ultimately, further investigations for the AKI were completed at the tertiary hospital. The HAGMA was suspected to be caused by the concurrent use of flucloxacillin and paracetamol. As a result of this, flucloxacillin was changed to cefazolin and the patient transferred again to a tertiary facility pending further investigations as well as suspected pulmonary embolism following reports of chest pain.
Investigations
Baseline before flucloxacillin
The initial working diagnosis was community-acquired pneumonia (pH of 7.38; pCO2 40 mm Hg; pO2 26 mm Hg; bicarbonate 23 mmol/L; anion gap 14 mmol/L). The patient reported having been treated for recurrent chest infections by her GP with oral antibiotics without improvement. On admission to hospital, her initial heart rate was 95 bpm, respiratory rate was 25 breaths per minute (tachypnoea) and O2 sat was 96% on room air. A chest X-ray was performed which showed consolidation in the right lower lobe that was consistent with the clinical presentation of pneumonia. Initially, the patient was treated with broad-spectrum piperacillin–tazobactam following the collection of relevant cultures. Sputum samples before transfer to tertiary facility grew S. aureus sensitive to flucloxacillin, cefazolin, clindamycin and co-trimoxazole. A urine sample showed Klebsiella pneumoniae sensitive to amoxicillin clavulanate, cefazolin, trimethoprim and gentamicin and resistant to ampicillin and nitrofurantoin. Blood cultures grew S. aureus that was sensitive to flucloxacillin and cefazolin while resistant to Penicillin G. It is worthy mentioning that S. aureus was grown on several sputum cultures in the 8 months preceding admission coinciding with the aforementioned recurrent chest infections. As the blood cultures grew S. aureus sensitive to flucloxacillin, intravenous flucloxacillin (2 g four times daily) was then commenced.
The patient was transferred to the closest tertiary hospital where she was reviewed by the infectious disease and respiratory teams. The final working diagnosis was methicillin-sensitive S. aureus (MSSA) bacteraemia secondary to a cavitating lower lobe pneumonia. CT chest and abdomen demonstrated right lower lobe pneumonia with cavitations. During this admission, she underwent transthoracic and trans-oesophageal echocardiograms which did not reveal any evidence of infective endocarditis. An MRI of the spine excluded discitis and osteomyelitis. Ultimately, the long-term steroid use for polymyalgia rheumatica was identified as a major contributing factor to immune suppression and a plan to wean steroids was formulated. Finally, a PICC was inserted and the plan was for ongoing intravenous flucloxacillin 2 g every 4 hours with ongoing infectious disease and respiratory reviews in addition to follow-up imaging in 4 weeks’ time. Flucloxacillin was planned to continue for a further 5 weeks via PICC on an 8 g/24 hours infuser that was monitored via HITH.
HAGMA cause identified
The patient was referred back to the regional hospital due to deteriorating renal function found on blood tests performed for the investigation of nausea while under HITH (table 1). A repeat chest CT scan showed a small focus of right lower lobe consolidation with small pulmonary cavitating nodules which is indicative of a potential secondary atypical infection.
Table 1 Electrolytes over time
At baseline before flucloxacillin PGA confirmed A day after flucloxacillin ceased One week after flucloxacillin ceased Unit Reference
Sodium 140 137 148 140 mmol/L 135–145
Potassium 3.9 2.8 4.2 3.8 mmol/L 3.5–5.2
Chloride 104 111 121 110 mmol/L 95–110
Bicarbonate 22 9 11 21 mmol/L 22–32
Anion gap 14 17 16 9 mmol/L 4–13
Urea 12.6 6.2 6.2 5.4 mmol/L 2.9–8.2
Creatinine 106 206 204 147 µmol/L 36–73
Urea/creatinine 119 30 30 37 40–100
eGFR 44 20 20 30 mL/min/1.73 m2 >60
eGFR, estimated glomerular filtration rate; PGA, pyroglutamic acidosis.
The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) with underlying significant high anion gap metabolic acidosis. At this point, PGA was suspected to be caused by flucloxacillin and paracetamol. The patient was found to have a blood pyroglutamic acid concentration of 7467 µmol/L and urine concentration of 1700 mmol/mol creatinine (<110 mmol/mol creatinine) a day after flucloxacillin was discontinued.
Prior to transfer to the tertiary facility, a chest X-ray was performed to investigate the reported chest pain, but there were no significant findings. A ventilation and perfusion scan was performed at the tertiary hospital and showed no evidence of a pulmonary embolism.
HAGMA resolved after cessation of flucloxacillin
A pyroglutamic acid level was able to be taken at the tertiary facility and the level came back at 7467 µmol/L (normal range is 20–50 µmol/L) and urinary level of 1700 mmol/mol creatinine (<110 mmol/mol creatinine). Cefazolin was adjusted for renal impairment and paracetamol was continued while admitted at the tertiary facility although ideally this should have been ceased.
The patient was then back-transferred to the regional hospital after her HAGMA had started to improve. It was decided to change her antibiotics to oral amoxicillin–clavulanic acid as she was nearing the completion of her intended course for MSSA bacteraemia. Paracetamol was continued for pain management although ideally should have been ceased to help resolve the HAGMA. Her condition continued to improve and HAGMA completely resolved before she was discharged home.
A third CT chest at the regional hospital showed that there was moderate improvement of the multifocal consolidation bilaterally. However, there was a new area of ground-glass calcification within the anterior segment of the right upper lobe which suggested a new focal infection.
A follow-up chest X-ray showed no significant consolidation.
Treatment
The HAGMA was initially of an unknown cause, so the patient was commenced on sodium bicarbonate 840 mg daily. The venous blood gas showed acidaemia (pH 7.26; pCO2 20 mm Hg; pO2 37 mm Hg; bicarbonate 9 mmol/L) indicating significant high anion gap metabolic acidosis (table 1). Usual causes for AKI and HAGMA were considered and excluded. Eventually, PGA was suspected to be caused by flucloxacillin and paracetamol with the risk factors being chronic kidney disease and advanced age.
The flucloxacillin was ceased and the patient was instead treated with amoxicillin and clavulanic acid. This was sufficient to resolve the HAGMA without the cessation of paracetamol or the institution of a NAC infusion (table 2). In retrospect, at the time, paracetamol could also have been ceased to help resolve the HAGMA.
Table 2 Venous blood gas analysis over time
At baseline before flucloxacillin PGA confirmed After a day flucloxacillin ceased Unit Reference
pH 7.38 7.26 7.44 – 7.35–7.45
pCO2 40 20 16 mm Hg 32–48
pO2 26 37 18 mm Hg 30–40
Bicarbonate 23 9 11 mmol/L 22–32
PGA, pyroglutamic acidosis.
Outcome and follow-up
The patient was discharged on amoxicillin and clavulanic acid and advised to complete an appropriate course. She was advised to undergo a repeat CT scan and was referred to the respiratory outpatient clinic. She was also advised to present to her GP for further investigations of macrocytic anaemia. For the ensuing months, as an outpatient her bicarbonate levels and kidney function remained at baseline.
Discussion
Pyroglutamic acidosis is a rarely recognised cause of HAGMA. The incidence of PGA is not known although it is likely to be underdiagnosed considering the high prevalence of risk factors. Those include advanced age, sepsis, malnutrition, uncontrolled diabetes, female gender, chronic liver disease, chronic kidney disease, iso-oxylopenicillin use and paracetamol use.11–17
PGA results from decreased glutathione, which causes increased production of pyroglutamic acid, and inhibition of 5-oxoprolinase, which decreases breakdown of pyroglutamic acid. When glutathione levels are depleted, the negative feedback on γ-glutamyl cysteine synthetase is diminished and production of pyroglutamic acid is favoured.16 Paracetamol contributes to cysteine deficiency through direct conjugation and glutathione deficiency via its metabolite N-acetyl benzoquinonemine that binds irreversibly to glutathione.18 Synthetic penicillins (iso-oxylopenicillin) such as flucloxacillin and dicloxacillin inhibit 5-oxoprolinase which prevents the degradation of pyroglutamic acid to glutamate, thereby contributing to pyroglutamic acidosis (refer to figure 2).19 20
Figure 2 γ-Glutamyl cycle and the effect of long-term paracetamol and flucloxacillin in promoting pyroglutamic acidosis.
In this case, the patient’s blood pyroglutamic acid level was 7467 µmol/L, which is significantly higher than previously detailed in other case reports. The urine pyroglutamic acid was 1700 mmol/mol creat (<110 mmol/mol creat). Nevertheless, it is presently unknown as to how the degree of elevation of PGA correlates to the symptoms or the degree of acidaemia. As such in this case, it was associated with moderate acidaemia.
As with other organic acids, pyroglutamic acid is excreted in the urine, leading to pyroglutamic aciduria.21 The patient had an AKI on the background of chronic kidney disease which decreases the elimination of pyroglutamic acid, further exacerbating the accumulation.
The diagnosis of PGA is often made on the basis of a medication history, arterial and venous acid–base analysis and exclusion of more common causes of HAGMA. Definitive diagnosis is based on plasma or urine pyroglutamic acid levels. However, these specific tests are not performed widely which restricts its implementation into clinical practice.22
The treatment and management of PGA-related HAGMA involves ceasing offending medications and commencing best supportive care. There have been cases where flucloxacillin has been substituted for alternative beta-lactam penicillins, which would support that PGA-related HAGMA occurs secondary to iso-oxylopenicillins and that other beta-lactams are safe to use in those instances.23–26 While flucloxacillin was ceased, in retrospect, paracetamol should have also been ceased. Some reports discuss the use of bicarbonate supplements to stabilise the pH, and NAC which has had some reported efficacy. However, the evidence to support the use of NAC in HAGMA is limited and the potential risks associated with NAC administration remain unclear.27 28 The benefits of NAC are not well established with risks of NAC administrations.29 30 Ultimately, ceasing or substituting the offending medications as well as best supportive cares seem to be sufficient in the treatment of PGA-related HAGMA.
Learning points
Paracetamol and iso-oxylopenicillins are commonly prescribed medications; therefore, it is important to be aware of adverse effects of co-administration.
Pyroglutamic acidosis (PGA) is a diagnosis of exclusion.
In the appropriate clinical context, definitive diagnosis is attained with a blood or urine level of pyroglutamic acid.
Cessation of flucloxacillin was sufficient in resolving the high anion gap metabolic acidosis (HAGMA) without an N-acetylcysteine infusion in this case.
In line with published literature, we recommend the cessation of both iso-oxylopenicillin and paracetamol. However, in this case, paracetamol was continued but still the HAGMA resolved.
Awareness of PGA is imperative to diagnosing and treating.
Contributors: AZI: conception and planning/design. GB: organisation, conduct, reporting and acquisition of data. BC: analysis and interpretation of data. HG: involved in the writing and proof-reading of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33419747 | 18,962,864 | 2021-01-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cholecystitis acute'. | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | ASPIRIN, CLOPIDOGREL BISULFATE, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33419958 | 19,412,273 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemobilia'. | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | ASPIRIN, CLOPIDOGREL BISULFATE, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33419958 | 19,412,273 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhagic ascites'. | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | ASPIRIN, CLOPIDOGREL BISULFATE, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhagic cholecystitis'. | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | ASPIRIN, CLOPIDOGREL BISULFATE, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
What was the administration route of drug 'ASPIRIN'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
What was the administration route of drug 'CLOPIDOGREL BISULFATE'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
What was the administration route of drug 'WARFARIN'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
What was the dosage of drug 'ASPIRIN'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | 100 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
What was the dosage of drug 'WARFARIN'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | 3 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
What was the outcome of reaction 'Cholecystitis acute'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | Recovered | ReactionOutcome | CC BY-NC-ND | 33419958 | 19,412,273 | 2021-01-09 |
What was the outcome of reaction 'Haemobilia'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | Recovered | ReactionOutcome | CC BY-NC-ND | 33419958 | 19,412,273 | 2021-01-09 |
What was the outcome of reaction 'Haemorrhagic ascites'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | Recovered | ReactionOutcome | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
What was the outcome of reaction 'Haemorrhagic cholecystitis'? | A Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy.
BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.
Background
Hemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.
Case Report
A 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.
On the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.
Discussion
Hemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].
Cholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.
The characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].
Many cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.
Conclusions
ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.
Conflicts of interest
None.
Figure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.
Figure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).
Figure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).
Figure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side. | Recovered | ReactionOutcome | CC BY-NC-ND | 33419958 | 19,399,124 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaphylactic reaction'. | Drug-induced anaphylaxis during general anesthesia in 14 tertiary hospitals in Japan: a retrospective, multicenter, observational study.
Since perioperative anaphylaxis occurs suddenly, and it can be life-threatening, anesthesiologists need to have sufficient knowledge of the epidemiology of perioperative anaphylaxis and appropriate coping strategies to deal with it. Recent studies conducted in Western countries reported the characteristics of perioperative anaphylaxis in each country. However, there are few studies of perioperative anaphylaxis in Japan. To bridge the gap between Japan and other countries, the data of 46 anaphylaxis patients at Gunma University Hospital and 13 neighboring hospitals between 2012 and 2018 were collected and analyzed. The recently developed clinical scoring system was combined with a skin test to include only cases with a definite diagnosis. The most common causative agents were sugammadex, followed by rocuronium, cefazolin, and antibiotics other than cefazolin. Furthermore, the characteristics of anaphylaxis for each causative drug were identified. Time from drug administration to appearance of the first symptom was the longest in the cefazolin group. The incidence of canceled operation was the highest in the rocuronium group. Although it is unclear whether the results of this study can apply to Japan as a whole, the information about the agents responsible for perioperative anaphylaxis and the characteristics of anaphylaxis due to each agent would be helpful to anesthesiologists.
Introduction
Intraoperative complications can be minimized by proper monitoring and medication based on relevant preoperative assessment. However, due to the difficulty of predicting the occurrence of anaphylaxis, the risk of developing perioperative anaphylaxis cannot be reduced even with these efforts. Although the severity of reactions ranges from mild to severe, in extreme cases, anaphylaxis may be fatal despite prompt recognition, prolonged adequate resuscitation, and treatment [1]. Therefore, anesthesiologists need to have sufficient knowledge of the epidemiology of perioperative anaphylaxis and appropriate coping strategies to deal with it.
Given these circumstances, large-scale epidemiological studies have recently been conducted in Western countries, and they suggested large differences in the characteristics of perioperative anaphylaxis among countries [2–7]. Unlike the situation in other countries, however, little research has been done in Japan. The last epidemiological survey of perioperative anaphylaxis in Japan was conducted 28 years ago [8]. To bridge the gap between Japan and other countries, we decided to collect and analyze the data of anaphylaxis occurring at Gunma University Hospital and 13 neighboring hospitals in the past 7 years. Since perioperative anaphylaxis is often difficult to diagnose, the recently developed clinical scoring system [9] was combined with a skin test to include only cases with a definite diagnosis. We expect that this research would enable us to recognize the characteristics of perioperative anaphylaxis occurring in Japan.
Materials and methods
This retrospective, observational study conformed to the standards of the Declaration of Helsinki and was approved by the ethics committee of Gunma University [identification (ID): 150034]. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (ID: 000022365). Some of the cases included in this study have already been presented in our previous reports, which had different perspectives from the present study [10–14].
The patients diagnosed with anaphylaxis between Jan 2012 and Dec 2018 in Gunma University Hospital and 13 Japanese tertiary hospitals were included in this study. Anaphylaxis was diagnosed only when the following two criteria were fulfilled: (1) evaluation using the clinical monitoring scoring system suggested the possibility of an immediate hypersensitivity reaction (net total score on the clinical grading scale ≥ 8) [9]; and (2) skin tests showed a positive reaction to any of the agents that the patient was exposed to during anesthesia. Patient information regarding the clinical background, the timing of symptom appearance, time from administration of the drug to appearance of the first symptom, types of clinical symptoms, net total score on the clinical grading scale, severity grade, and outcome was collected. The clinical symptoms were classified into four categories, including cardiovascular, respiratory, cutaneous, and gastrointestinal. The severity of clinical symptoms was assessed using the ring and Messmer scale [15].
Continuous variables are reported by the median and interquartile range values. The differences in continuous variables among agents were analyzed with one-way ANOVA or Kruskal–Wallis one-way ANOVA on ranks. Categorical variables were analyzed with Fisher’s exact test. Sigma plot 14.0 (Systat Software Inc, San Jose, CA) or R ver. 3.3.3 was used for the analyses. Differences were considered significant at a p value < 0.05.
Results
A total of 49 patients with suspected anaphylaxis due to their clinical symptoms were initially investigated. Three of these patients had negative skin test reactions for all drugs to which they had been exposed during anesthesia; therefore, 46 patients were ultimately included in this study (Table 1). The common causative agents were as follows: sugammadex (n = 13, 28.3%), rocuronium (n = 10, 21.7%), cefazolin (n = 8, 17.4%), and antibiotics other than cefazolin (n = 7, 15.2%) (Table 2, Supplemental Fig. 1).Table 1 Clinical backgrounds, causative agents, timing and onset of the appearance of symptoms, anaphylactic symptoms, severity grades, clinical scores, and outcomes in patients with perioperative anaphylaxis
Patient no. Age (years) Sex Causative agent Timing Onset (min) Symptoms Severity grade Clinical score Cancelled operation Delayed extubation
1 75 F Sugammadex End 3 Ca, Cu 3 25 − +
2 34 M Sugammadex End 1 Ca, Cu 2 19 − −
3 13 M Sugammadex End 5 Ca, Cu, Re 3 30 − +
4 65 M Sugammadex End < 1 Ca, Cu, Re 3 27 − +
5 39 M Sugammadex End 8 Ca, Cu 2 17 − −
6 62 M Sugammadex End 3 Ca, Ga 3 13 − −
7 64 F Sugammadex End 3 Ca, Cu 2 21 − +
8 33 F Sugammadex End 5 Ca, Cu 2 19 − −
9 46 F Sugammadex End 3 Ca, Cu, Re 3 30 − +
10 66 M Sugammadex End 3 Ca, Cu, Re 3 28 − −
11 19 F Sugammadex End 3 Ca, Cu, Re 3 30 − +
12 42 F Sugammadex End 3 Ca, Cu, Ga 3 15 − −
13 55 M Sugammadex End 3 Ca, Cu 3 17 − −
14 41 F Rocuronium Induction < 1 Ca, Re 4 35 + −
15 52 F Rocuronium Induction 5 Ca, Cu, Re 3 28 − −
16 56 F Rocuronium Induction 5 Ca, Re 2 22 − +
17 74 F Rocuronium Maintenance 20 Ca, Cu 3 11 − −
18 16 M Rocuronium Induction 5 Ca, Cu 3 23 + −
19 72 M Rocuronium Induction 3 Ca 3 17 + −
20 38 F Rocuronium Induction 3 Ca, Cu, Re 2 22 + +
21 83 F Rocuronium Induction 10 Ca, Cu 2 17 + −
22 78 F Rocuronium Induction 10 Ca, Cu, Re 2 19 − −
23 36 M Rocuronium Induction 3 Ca, Cu, Re 2 28 + −
24 71 F Cefazolin Maintenance 10 Ca, Cu 3 21 + +
25 26 F Cefazolin Maintenance 2 Ca, Re 3 26 + +
26 67 F Cefazolin Maintenance 3 Ca, Cu 2 21 − −
27 7 F Cefazolin Maintenance 10 Ca, Re 3 22 + −
28 33 F Cefazolin Maintenance 20 Ca, Cu 3 12 − −
29 77 M Cefazolin Maintenance 10 Ca, Cu, Re 3 20 − −
30 51 M Cefazolin Maintenance 10 Ca, Cu 3 19 + −
31 14 M Cefazolin Maintenance 10 Ca, Cu 2 24 − −
32 56 M Cefoperazone/Sulbactam Maintenance 5 Ca, Re 4 32 − +
33 49 F Cefmetazole Maintenance 5 Ca, Cu 3 23 − −
34 36 F Cefmetazole Maintenance 5 Ca, Cu 2 17 − −
35 77 M Vancomycin Maintenance 5 Ca, Cu 4 28 − −
36 86 M Ceftriaxone Maintenance 5 Ca, Cu 3 23 + −
37 44 F Cefotiam Maintenance 10 Ca, Cu 3 19 + −
38 25 M Fosfomycin Maintenance 5 Ca, Cu, Re 3 18 + −
39 54 M Lidocaine Induction < 1 Ca, Cu 3 12 − −
40 42 F Mepivacaine Induction 10 Ca, Cu 3 13 − −
41 21 M Flurbiprofen End 10 Ca, Cu 2 20 − −
42 61 F Propofol Induction < 1 Cu, Re 2 17 − −
43 66 M Fibrin sealant Maintenance 5 Ca, Cu 3 13 − −
44 49 F Fibrin sealant Maintenance 10 Ca, Cu 2 9 − −
45 80 F Atropine Induction 3 Ca, Cu 2 13 − −
46 50 M Iopamidol Maintenance 10 Ca 3 9 − −
The timing of symptom appearance was classified into three categories, including induction, maintenance, and end of anesthesia. The induction of anesthesia refers to within 10 min after the start of anesthesia. The end of anesthesia means from the end of surgery to the end of anesthesia. Maintenance of anesthesia is the period between induction of anesthesia and the end of anesthesia. The onset indicates time from drug administration to the appearance of the first symptom. The severity of clinical symptoms was assessed by the Ring and Messmer scale [15]. All patients had a clinical score of 8 or above, suggesting possible anaphylaxis [9]. Delayed extubation was defined as when the patient was extubated after leaving the operating room, or when it took more than two hours from the end of surgery to extubation even in the operating room
M male, F female, Ca cardiovascular signs, Cu cutaneous signs, Re respiratory signs, Ga gastrointestinal signs
Table 2 Characteristics of perioperative anaphylaxis classified by causative agent
Sugammadex Rocuronium Cefazolin Antibiotics Miscellaneous All
Number of patients (%) 13 (28.3) 10 (21.7) 8 (17.4) 7 (15.2) 8 (17.4) 46 (100.0)
Background
Female (%) 6 (46.2) 7 (70.0) 5 (62.5) 3 (42.9) 4 (50.0) 25 (54.3)
Male (%) 7 (53.8) 3 (30.0) 3 (37.5) 4 (57.1) 4 (50.0) 21 (45.7)
Age (years) 47.2 (19.2) 54.6 (22.0) 43.3 (27.0) 53.3 (21.8) 52.9 (17.5) 50.0 (20.9)
Timing
Induction (%) 0 (0.0) 9 (90.0)a 0 (0.0) 0 (0.0) 4 (50.0) 13 (28.3)
Maintenance (%) 0 (0.0) 1 (10.0) 8 (100.0)b 7 (100.0)c 3 (37.5) 19 (41.3)
End (%) 13 (100.0)d 0 (0.0) 0 (0.0) 0 (0.0) 1 (12.5) 14 (30.4)
Onset (min) 3.0 (1.0) 5.0 (7.0) 10.0 (5.3)e 5.0 (0.0) 7.5 (8.5) 5.0 (7.0)
Symptom
Cardiovascular (%) 13 (100.0) 10 (100.0) 8 (100.0) 7 (100.0) 7 (87.5) 45 (97.8)
Respiratory (%) 5 (38.5) 6 (60.0) 3 (37.5) 2 (28.6) 1 (12.5) 17 (37.0)
Cutaneous (%) 12 (92.3) 7 (70.0) 6 (75.0) 6 (85.7) 7 (87.5) 38 (82.6)
Gastrointestinal (%) 2 (15.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3)
Clinical score 22.4 (6.2) 22.2 (6.8) 20.6 (4.1) 22.9 (5.5) 13.3 (3.7)f 20.5 (6.4)
Severity grade 3.0 (1.0) 2.5 (1.0) 3.0 (0.8) 3.0 (1.0) 2.5 (1.0) 3.0 (1.0)
Outcome
Cancelled operation (%) 0 (0.0) 6 (60.0)g 4 (50.0) 3 (42.9) 0 (0.0) 13 (28.3)
Delayed extubation (%) 6 (46.2) 2 (20.0) 2 (25.0) 1 (14.3) 0 (0.0) 11 (23.9)
“Antibiotics” refers to antibiotics other than cefazolin. Categorical variables are shown as the actual numbers, and percentages are shown in parentheses. Since age and clinical score were normally distributed, they are shown as means, and standard deviations are shown in square brackets. For onset and severity grade, the median values and interquartile ranges are shown. The timing of symptom appearance was classified into three categories, including induction, maintenance, and end of anesthesia. The induction of anesthesia refers to within 10 min after the start of anesthesia. The end of anesthesia means from the end of surgery to the end of anesthesia. Maintenance of anesthesia is the period between induction of anesthesia and the end of anesthesia. The onset indicates the time from drug administration to the appearance of the first sign. The accuracy of anaphylaxis diagnosis was assessed using the clinical grading scale [9]. The severity of clinical signs was assessed by the Ring and Messmer scale [15]. Delayed extubation was defined as when the patient was extubated after leaving the operating room, or when it took more than two hours from the end of surgery to extubation even in the operating room. The symbols indicate significant differences between groups, and p values were 0.005 or less unless otherwise specified
aRocuronium vs. sugammadex, cefazolin, and antibiotics; bCefazolin vs. rocuronium and sugammadex
cAntibiotics vs. rocuronium and sugammadex
dSugammadex vs. all other groups
eCefazolin vs. sugammadex (p < 0.05)
fMiscellaneous vs. sugammadex, rocuronium, cefazolin, and antibiotics (p < 0.05)
gRocuronium vs. sugammadex (p < 0.05)
To investigate the characteristics of anaphylaxis for each causative agent, patients were divided into the following five groups: sugammadex, rocuronium, cefazolin, antibiotics other than cefazolin, and miscellaneous. Although there were no significant differences in sex, age, clinical symptoms, and severity grade, the characteristics of anaphylaxis for each causative drug emerged (Table 2). First, the timing of symptom appearance had distinct characteristics. That is, rocuronium-induced anaphylaxis occurred during induction of anesthesia, antibiotic-induced anaphylaxis occurred during maintenance of anesthesia, and sugammadex-induced anaphylaxis occurred at the end of anesthesia. There was only one exception. Second, the time from drug administration to the appearance of the first symptom was the longest in the cefazolin group, significantly longer than in the sugammadex group (p < 0.05, one-way ANOVA with the post hoc Dunn’s test). Third, the incidence of cancelled operation was the highest in the rocuronium group, significantly higher than in the sugammadex group (p < 0.05, Fisher’s exact test with the post hoc Bonferroni test).
Discussion
This study summarized the causative agents in 46 cases of perioperative anaphylaxis that occurred in the past 7 years and the characteristics of each causative agent.
Sugammadex was the most common causative agent of perioperative anaphylaxis, which differed from past studies conducted in foreign countries and may be a feature of anaphylaxis occurring in Japanese hospitals. Although various factors are considered, high usage of sugammadex in Japan might be one of the reasons [13, 16]. This situation appears to be different from other countries. For example, the amount of sugammadex used per case of general anesthesia in Japan is expected to be 22.8 times greater than that in the UK [13].
Regarding the neuromuscular blocking agents (NMBAs), rocuronium is also the top causative drug in most countries other than Japan. For example, in Australia, rocuronium was responsible for 56% of cases of NMBA-induced anaphylaxis, succinylcholine 21%, and vecuronium 11% [17]. In the present study, however, no anaphylaxis was observed due to NMBAs other than rocuronium, which might again reflect the high use of rocuronium in Japan [13].
Even greater differences between Japan and other countries may be seen for antibiotic-induced anaphylaxis. Although there are few data on perioperative antibiotics used in each country, NAP6 data from a study conducted in the UK are available: gentamicin was used most often (34.5%), followed by amoxicillin/clavulanic acid (29.8%) and cefuroxime (23.7%) [2]. Although there are no national data on perioperative antibiotic use in Japan, a survey of perioperative drugs we recently conducted at four tertiary hospitals showed that cefazolin was used in 69% of general anesthesia cases, followed by cefmetazole in 12% (unpublished data).
Taken together, the reason for the differences in the causative agents of perioperative anaphylaxis in the current study compared to previous studies might be partially explained by the differences in the drugs used. The fact that sugammadex, rocuronium, and cefazolin account for 67% of causative agents (31 of 46 cases) in perioperative anaphylaxis in the present study might be a prominent feature of perioperative anaphylaxis in Japan.
Although the results of the present study suggest that the timing of anaphylaxis development is clearly different by drug (Table 1), this does not necessarily mean that the causative drug can be determined by the timing alone. For example, drugs other than rocuronium, including lidocaine and propofol, were also included in the “Induction of anesthesia” category (Table 1). An informed guess, which is based on the relationship between the timing of substance exposure and that of symptom appearance, is not a reliable way of determining the cause of a supposed allergic reaction [18]. We would emphasize that the cause of anaphylaxis should be identified by allergy tests such as skin tests. Otherwise, many patients would be at unnecessary risk.
The median time of onset was the latest in the cefazolin group (Table 2). In some cases with a delayed onset, the patient’s body might have already been covered with a surgical drape when the signs of anaphylaxis appeared.
In rocuronium-induced anaphylaxis cases, surgery was cancelled in 60%, the highest rate among the groups. In general, skin testing is recommended to both find a causative agent and identify alternative NMBAs, especially in cases where re-operation is required [16]. Since in patients with anaphylaxis due to rocuronium, skin tests were reported to be positive in 44% for succinylcholine, 40% for vecuronium, and 5% for cisatracurium, cisatracurium is recommended for use as an alternative NMBA [17]. In countries such as Japan where cisatracurium is not available, anesthesia without NMBAs should be considered [16, 19].
This study has several limitations. First, since the location of the participating hospitals was limited to the Kanto region, it is unclear whether the results of this study can be applied to Japan as a whole. Second, since the drugs used at each hospital during the study period were not investigated, the incidence of anaphylaxis for each drug is unknown. Future studies, including the ongoing national epidemiologic study, the Japanese Epidemiological Study for Perioperative Anaphylaxis (JESPA), will address these issues.
In conclusion, the information obtained from the present study regarding the agents responsible for perioperative anaphylaxis and the characteristics of anaphylaxis due to each agent would be useful to anesthesiologists.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (JPG 799 KB)
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The authors would like to thank Dr. Yukinari Tomita at Isesaki Municipal Hospital, Dr. Akihiro Tomioka at JCHO Gunma Chuo Hospital, Dr. Nagahide Yoshida at Gunma Saiseikai Maebashi Hospital, Dr. Kenichiro Takahashi at Japanese Red Cross Ashikaga Hospital, Dr. Toshifumi Takahashi at Gunma Prefectural Cancer Center, Dr. Mutsumi Uchiyama at Saitama Cancer Center, Dr. Iwao Watanabe at Ogikubo Hospital, Dr. Miyuki Takahashi at Jichi Medical University, Dr. Masayuki Ueno at Saiseikai Utsunomiya Hospital, Dr. Makoto Sudo at Tatebayashi Public Hospital, Dr. Kazuaki Hagiwara at Saku Central Hospital Advanced Care Center, and Dr. Toshie Shiraishi at Yotsuya Medical Cube for their leadership as research representatives in each hospital and for their kind advice regarding the interpretation of cases.
Author contributions
Study concept/design: all authors. Data collection, analysis, and interpretation: TH and TT. Writing of the paper and responsibility for its contents: all authors.
Funding
This study was supported by the Gunma Foundation for Medicine and Health Science, and the Japan Society for the Promotion of Science KAKENHI 18K08809.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest. | LIDOCAINE | DrugsGivenReaction | CC BY | 33420820 | 19,246,162 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Differentiation syndrome'. | The impact of ICAM-1, CCL2 and TGM2 gene polymorphisms on differentiation syndrome in acute promyelocytic leukemia.
BACKGROUND
Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are well-tolerated and effective treatments for Acute Promyelocytic Leukemia (APL), Differentiation Syndrome (DS) is a lethal side effect in some patients. The pathogenesis of DS is complex and not well understood; however, it is considered as an inflammatory response due to cytokines release of differentiated cells. Moreover, adhesion molecules that are widely expressed on the surface of differentiated cells and gene expression changes of transglutaminase2 (TGM2) are mechanisms involved in the development of DS. The purpose of this study was to assess the association of single nucleotide polymorphisms (SNP) of Intercellular Adhesion Molecule-1 (ICAM-1), chemokine (C-C motif) ligand 2 (CCL2) and TGM2 as inflammatory factors with differentiation syndrome susceptibility.
METHODS
DNA was extracted from 133 APL patients and 100 normal controls. Assessment according to the PETHEMA criteria revealed that 13.5% of these patients experienced differentiation syndrome. Tetra-ARMS PCR and PCR-RFLP were done to amplify DNA fragments in APL patients with and without DS. Then DNA sequencing was done to validate the results. SNPStats, SPSS and Finch TV were used to analyze the results.
RESULTS
A significant correlation was found between rs4811528 in the TGM2 gene and differentiation syndrome susceptibility (P = 0.002, 95% CI = 1.74-18.81, OR = 5.72) while rs5498 in ICAM-1, rs1024611 in CCL2, and rs7270785 in TGM2 genes showed no correlation with differentiation syndrome. The G allele of rs7270785 and rs4811528 showed a haplotypic association with differentiation syndrome (P = 0.03, 95% CI = 1.13-13.86, OR = 3.96).
CONCLUSIONS
AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.
Background
Acute Promyelocytic Leukemia (APL) is characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17, t (15; 17) (q21; q22), which results in a fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RAR alpha). PML/RARα homodimers inhibit the expression of differentiation genes in granulocytes [1, 2]. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), especially when combined compared to either one alone, are the most effective drugs for the treatment of APL, which induce the degradation of chimeric oncoprotein PML/RARα and APL cell differentiation [3, 4]. ATRA/ATO treatment can induce differentiation syndrome (DS) or retinoic acid syndrome (a life-threatening complication) in some patients [5]. According to the PETHEMA (Programa para el Tratamiento de Hemopatías Malignas) criteria, the presence of one or more of the following features may indicate a diagnosis of DS: hyperleucocytosis, respiratory distress, unexplained fever, hypotension, weight gain more than 5 kg, acute renal failure, and a chest radiograph demonstrating pericardial effusion or pulmonary infiltrates [6–9]. The molecular and cellular mechanisms of DS are not fully known; however, it is believed that administration of ATRA/ATO leads to a systemic inflammatory response syndrome (SIRS) and massive gene expression changes in differentiating blast cells [9–11]. The proposed mechanisms include changes in the adhesion molecules, cytokine secretion, and enzymes during ATRA/ATO induced differentiation such as Intercellular Adhesion Molecule-1(ICAM-1), monocyte chemoattractant protein-1 (MCP-1/CCL2), and type-2 transglutaminase (TGM2/TG2) [10, 12–14]. ICAM-1 (CD54) is a single chain 76–110 kDa glycoprotein and a member of the Ig superfamily located on chromosome 19p13 [15], MCP-1/CCL2 is a CC chemokine located on chromosome 17q11 [16], and TGM2 is a 74–80 kDa protein and a member of the transglutaminase family located on chromosome 20q11–12 [17, 18]. Single Nucleotide Polymorphisms (SNPs) SNPs are variations in the DNA sequence. SNPs are helpful in determining how individuals respond to diseases or interact with drugs and therapeutic procedures. Many studies have shown associations between polymorphisms and inflammatory disorders [19–21]. One study found an association between the AA genotype at ICAM-1 Exon 6 (E469K) and DS [3]. Considering the possible role of the polymorphisms of cell adhesion molecules, chemokines, and transglutaminase in DS pathogenesis, the aim of this study was to investigate the association of rs1024611 in CCL2, rs5498 in ICAM-1, and rs7270785 and rs4811528 in TGM2 with the development of differentiation syndrome in patients treated with ATRA/ATO.
Methods
Patients characteristics
From 2012 to 2017, patients with APL who referred to the Hematology, Oncology, and Stem Cell Transplantation Research Center of Shariati hospital, Tehran, Iran were studied. All patients received ATRA-ATO as reported previously [22]. One hundred and thirty-three APL patients were selected based on availability of patient samples. According to the PETEHMA criteria (fever ≥38 °C, weight gain> 5 kg, hypotension, dyspnea, LQTS (Long QT Syndrome) and acute renal failure), Eighteen selected APL patients were diagnosed with differentiation syndrome after receiving ATRA/ATO. Samples from 100 healthy volunteers were used as controls. The study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethics Code: IR.TUMS.SPH.REC.1397.269) and written informed consent was obtained from all participants.
DNA isolation
The genomic DNA of the samples was extracted from their peripheral blood in tubes containing ethylene-diamine tetra acetic acid (EDTA) anticoagulants using the standard salting-out method. The concentration and the purity of the DNA samples were evaluated with a Nano Drop device (Thermo Fisher Scientific, USA).
Tetra-ARMS PCR (tetra-primer ARMS PCR)
The amplification-refractory mutation system polymerase chain reaction (Tetra-ARMS PCR) was used for detection of rs5498 in ICAM-1 and rs7270785 and rs4811528 in TGM2 with appropriate primer sets Table 1. The reaction was performed in a total volume of 15 μl, containing 1 μl genomic DNA (60–80 ng/μl), 7.5 μl 1× Master Mix PCR (Ampliqon, Denmark), optimum forward and reverse inner primer ratio for rs5498, rs4811528 and rs7270785 (1:2, 1:2 and 1:4, respectively (10 pmol)), and 0.2–0.5 μM of each outer primer. The optimum PCR condition was 95 °C for 3 min followed by 35 cycles (95 °C for 15 s, 62 °C for 20 s, and 72 °C for 20 s in rs5498; 95 °C for 15 s, 62 °C for 15 s, and 72 °C for 25 s for rs4811528; and 95 °C for 15 s, 68 °C for 20 s, and 72 °C for 20 s for rs7270785) and a final extension at 72 °C for 6 min. To visualize the results, 10 μl PCR product was run on a 2% agarose gel containing 3 μl loading dye.
Table 1 The primer sequences used for gene PCR
SNP ID Primer sequences Product size (bp)
rs5498 F inner GAGCACTCAAGGGGAGGTCACCCTCG G allele (189)
R inner TCACTCACAGAGCACATTCACGGTCACATT A allele (274)
F outer ATCTCATCGTGTTTTTCCAGATGGCCCC Control band (407)
R outer CCCATTATGACTGCGGCTGCTACCACA
rs4811528 F inner ATAAACCTTGGCAAGCTCAAGGTCAGGGTT A allele (179)
R inner CACTCCTCCCACCTTAAGGGCTTCTCC G allele (259)
F outer GCTGTGTTGCTGTGTGAGCCTGGATAAG Control band (383)
R outer TGGAATAGTCGATGGTGAGCAGGAGACC
rs7270785 F inner CTTATCTCAAACCATAACCAACCTGCACC T allele (201)
R inner CAAGCTACAATGTTCCCACACAGGAGCA G allele (291)
F outer CAAGCTACAATGTTCCCACACAGGAGCA Control band (435)
R outer CTTCTCCAATTGTCTGGGCAGCGTAGTG
rs1024611 F outer GGCTGAGTGTTCACATAGGCTTCTGAGT Control band (281)
R outer AACTTCCAAAGCTGCCTCCTCAGAGT
F Forward, R Reverse
PCR-RFLP
The CCL2 polymorphism (rs1024611) was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using forward and reverse primers (Table 1). The reaction was performed in a total volume of 15 μl, containing 1 μl genomic DNA (60–80 ng/μl), 7.5 μl 1× Master Mix PCR (Ampliqon, Denmark), and 0.3 μM of each outer primer. PCR was performed by denaturing the samples at 95 °C for 3 min followed by 40 cycles including 95 °C for 15 s, 64 °C for 20 s, 72 °C for 25 s, and final extension at 72 °C for 6 min. For RFLP analysis, the PCR product was digested with 10 U/ μl PVUП and 10 x buffer G (Thermo Scientific, Massachusetts, United States) and incubated at 37 °C for 16 h. The digested PCR products were separated on a 2% agarose gel.
Validation assay
DNA sequencing was done to validate the results. The same outer primers of Tetra-ARMS PCR and PCR-RFLP in conventional PCR were used to amplify the regions containing SNPs. Then, the cycle sequencing reaction was done using the Big Dye Terminator v3.1 Cycle Sequencing kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s instructions and the samples were sequenced using the 3130 xl Genetic Analyzer ABI.
Statistical analysis
The Hardy-Weinberg equilibrium (HWE) was applied to assess the deviation of the genotype or allele frequency. The demographic and hematologic data were distributed normally. Pearson’s Chi square, Mann–Whitney U-test, and t-test were used for statistical comparison. The SPSS version 20.0 (IBM, NY, USA) was used for data analysis. Multiple logistic regression models (codominant, dominant, recessive, over dominant and log-additive) were applied to analyze the correlation between the SNP data and disease phenotype (odds ratio) with 95% confidence interval was calculated using the SNPStats software. P values less than 0.05 were considered significant. The Finch TV software version 1.4.0 was used to interpret the sequencing results.
Results
Patients ‘baseline characteristics
One hundred and thirty-three APL patients (74 females and 59 males) with a mean age of 36 ± 13.9 years and 100 healthy volunteers (51 females and 49 males) with a mean age of 34 ± 13.5 years were included in the study.
There were no significant differences between APL patients and healthy controls (p value < 0.05). Table 2 presents demographics and laboratorial findings of APL patients, with and without DS. According to this table, no significant differences were detected between the two groups.
Table 2 Demographics and laboratorial findings of APL patients with and without DS
Characteristics DS No DS P value
Number of samples 18 115
Gender (Male/Female) 7/11 52/63 0.6
Age (years) 37.8 ± 15.8 34.6 ± 13 0.4
WBC counts (/μl*103) 61.3 ± 9.9 65.5 ± 12.2 0.4
Hb (g/dl) 1.7 ± 8 2.6 ± 9 0.1
Platelets (/μl*103) 53.4 ± 45 57.2 ± 76 0.2
Values presented as mean (±SD), Hb Hemoglobin
Electrophoresis and sequencing results
The product of the tetra-primer ARMS PCR specific for rs5498 contained 3 fragments (407 bp, 274 bp and 189 bp) in the AG heterozygous genotype and 2 fragments in the homozygous mutant and wild types (GG resulting in 189 bp and 407 bp fragments, and AA resulting in 274 bp and 407 bp fragments) Fig. 1a. In rs7270785, the TG heterozygous genotype contained 3 fragments (435 bp, 291 bp and 201 bp), the GG homozygous mutant genotype contained 2 fragments (435 bp and 291 bp), and the TT homozygous wild type contained 2 fragments (435 bp and 201 bp) Fig. 1b. In rs4811528, the AG heterozygous genotype had 3 fragments (383 bp, 259 bp and 179 bp), the GG mutant homozygous genotype had 2 fragments (383 bp and 259 bp), and the AA homozygous wild type had 2 fragments (383 bp and 179 bp) Fig. 1c. For rs1024611, the amplified fragment length was 281 bp. Digestion with PVUП produced 3 fragments of 281 bp, 160 bp and 121 bp in the CT heterozygous genotype and 2 fragments of 160 bp and 121 bp in the CC homozygous mutant genotype while the TT homozygous wild type remained uncut Fig. 1d. A heterozygous sample of each SNP was selected that contained both mutant and wild type alleles; then, DNA sequencing confirmed the results obtained by T-ARMS PCR.
Fig. 1 Agarose gel electrophoresis of genotype variation of rs5498, rs7270785, rs4811528 and PCR-RFLP for rs1024611. Genotype variation of rs5498 determined by control fragment (407 bp), specific fragment of A allele (274 bp) and G allele (189 bp) a. Genotype variation of rs7270785 determined by control fragment (435 bp), specific fragment of G allele (291 bp) and T allele (201 bp) b. Genotype variation of rs4811528 determined by control fragment (383 bp), specific fragment of G allele (259 bp) and A allele (179 bp) c. For rs1024611, 1 represent negative control; 2 (undigested) and 3 (digested) represent T allele (281 bp);4 (undigested) and 5 (digested) represent C allele (160 bp and 121 bp); 6 (undigested) and 7 (digested) represent T and C allele (281 bp, 160 bp and 121 bp) d
Distribution of genotype and allele frequency
The genotype and allele frequencies for rs5498, rs4811528, rs7270785, and rs1024611 polymorphisms in case and control groups are presented in Table 3. The distribution of genotypes was consistent with HWE in both groups (P > 0.05). The frequency of the genotypes of TGM2 gene polymorphism (rs4811528) was AG = 44%, AA = 37%, and GG = 19% in 133 patients with APL and AA = 48%, AG = 41%, and GG = 11% in 100 controls.
Table 3 Genotypes and allele frequencies of polymorphisms analyzed in APL Patients and controls
APL Patients controls
SNP ID Genotype (N) Genotype Frequency (%) Allele (N) Allele Frequency (%) Genotype Genotype Frequency (%) Allele (N) Allele Frequency (%)
rs5498 AA (39) 29 A (150) 56 AA 30 A (112) 56
AG (72) 54 G (116) 44 AG 52 G (88) 44
GG (22) 17 GG 18
rs4811528 AA(50) 37 A (158) 59 AA 48 A (137) 68
AG (58) 44 G (108) 41 AG 41 G (63) 32
GG (25) 19 GG 11
rs7270785 TT (38) 29 T (148) 56 TT 25 T (108) 54
TG (72) 54 G (118) 44 TG 58 G (92) 46
GG (23) 17 GG 17
rs1024611 TT (61) 46 T (181) 68 TT 54 T (144) 72
TC (59) 44 C (85) 32 TC 36 C (56) 28
CC (13) 10 CC 10
Correlation of ICAM-1, CCL2 and TGM2 polymorphisms with differentiation syndrome in APL patients
Five genetic models (codominant, dominant, recessive, over dominant and log-additive) were applied to analyze the associations between ICAM-1, CCL2 and TGM2 polymorphisms and differentiation syndrome in patients with APL. The results of the genetic models showed that TGM2 polymorphism (rs4811528) was significantly associated with susceptibility to differentiation syndrome [codominant (OR = 5.61; 95% CI = 1.53–20.48, P = 0.009), dominant (OR = 5.72; 95% CI = 1.74–18.81, P = 0.002), over dominant (OR = 4.06; 95% CI = 1.14–14.44, P = 0.02), and log-additive (OR = 3.78; 95% CI = 1.37–10.44, P = 0.004)] Table 4. There was no significant association between ICAM-1 (rs5498), CCL2 (rs1024611), and TGM2 (rs7270785) polymorphisms and DS (data not shown). The 2-SNP haplotypes analysis also revealed a haplotypic association between the rs7270785–rs4811528 haplotypes of TGM2 gene with DS development in G allele (OR = 3.96; 95% CI = 1.13–13.86, P = 0.033) Table 5.
Table 4 Analysis of association of TGM2 polymorphism (rs4811528) with the development of DS in APL patients
Model Genotype DS (%) No DS (%) OR (95% CI) P-value AIC BIC
Codominant A/A 13 (72.2) 37 (32.2) 1.00 0.0096 90.2 104.7
A/G 4 (22.2) 54 (47) 5.61 (1.53–20.48)
G/G 1 (5.6) 24 (20.9) 6.14 (0.70–53.45)
Dominant A/A 13 (72.2) 37 (32.2) 1.00 0.0023 88.2 99.8
A/G-G/G 5 (27.8) 78 (67.8) 5.72 (1.74–18.81)
Recessive A/A-A/G 17 (94.4) 91 (79.1) 1.00 0.24 96.2 107.7
G/G 1 (5.6) 24 (20.9) 3.03 (0.36–25.25)
Over dominant A/A-G/G 14 (77.8) 61 (53) 1.00 0.02 92.1 103.6
A/G 4 (22.2) 54 (47) 4.06 (1.14–14.44)
Log-additive – – – 3.78 (1.37–10.44) 0.004 89.2 100.8
AIC Akaike Information criterion, BIC Bayesian Information
Table 5 Analysis of Haplotypic effect of rs4811528 and rs7270785 with the development of DS in APL patients
rs7270785 rs4811528 Frequency OR (95% CI) P-value
T A 0.43 1.00 0.033
G G 0.27 3.96 (1.13–13.86)
G A 0.17 1.47 (0.55–3.95) 0.45
T G 0.13 6.06 (0.67–54.75) 0.11
Discussion
Differentiation syndrome (DS) is a life-threatening complication characterized by respiratory distress, unexplained fever, hypotension, weight gain, interstitial pulmonary infiltrates, pleural or pericardial effusion, and acute renal failure as described by Frankel et al. in 1992 [7, 23]. Although the pathogenesis of DS is complex and not well understood, several molecular and cellular mechanisms are involved in the development of DS. ATRA is thought to (a) lead to the release of a variety of cytokines (especially inflammatory cytokines) by differentiating blast cells and (b) induce changes in the adhesive properties of blasts cells as well as massive changes in gene expression, including downregulation of cell proliferation of related genes and induction of genes involved in immune function [9, 24]. Finally, ATRA induces a systemic inflammatory response syndrome (SIRS) that manifests as fever, tachycardia and tachypnea and can progress to shock if left untreated [9]. The incidence of DS in APL patients ranges from 2 to 27%, possibly due to the heterogeneity and range of clinical symptoms as well as inaccuracy of diagnostic criteria [25]. In the current study, DS was diagnosed in 18 of 133 APL patients (13.5%) according to the PETEHMA criteria, including fever (temperature ≥ 38 °C), weight gain> 5 kg, hypotension, dyspnea, long QT syndrome, and acute renal failure after taking ATRA/ATO. This is the first study of the role of several polymorphisms (ICAM-1, CCL2 and TGM2 genes) in the susceptibility of APL patients receiving ATO/ATRA to differentiation syndrome. MCP-1 regulates the migration of monocytes/macrophages to tissues and is required for response to inflammation and routine immunological surveillance of tissues [26]. An A to G single nucleotide polymorphism (SNP) in the CCL2 enhancer region (rs1024611, originally designated as –2518G or –2578G) has been associated with several chronic inflammatory conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis [26–28]. In the present study, no association was found between this polymorphism and the development of differentiation syndrome. ICAM-1 is involved in cell adhesion and signaling, plays an important role in tumor progression and tumorigenesis, specifically by facilitating tumor invasion, and is associated with susceptibility to many cancers, including acute promyelocytic leukemia (APL) [14, 15]. Dore et al. found an association between development of DS and the AA genotype at codon 469 of ICAM-1 [3]. However, the present study showed no significant association between exon 6 (E469K) of ICAM-1 polymorphism and DS. The inclusion and exclusion criteria of the patients with DS and the prescribed medicines were different between the present study and the study by Dore et al. Type-2 transglutaminase (TGM2/TG2) is emerging as a multifunctional enzyme that is capable of promoting specialized enzyme functions under regulation by allosteric effectors depending on its cellular location such as angiogenesis, cell growth/differentiation, and cell death [17, 18]. TGM2 acts as a G protein in signal transduction processes and is involved in the pathophysiology of various inflammatory conditions. TGM2 is associated with 329 diseases, including immune system, endocrine, metabolic, cardiovascular, epidermal, renal and hematological diseases [17]. Bradford et al. genotyped eight SNPs (rs2076380, rs7270785, rs4811528, rs2284879, rs6023526, rs2268909, rs17789815 and rs1555074) related to the TGM2 gene in individuals with schizophrenia in a British population. The rs7270785–rs4811528 haplotypes showed the strongest association with schizophrenia, and the authors suggested that the TGM2 gene might be involved in schizophrenia in the British population [12]. Wang et al. found no genetic association between four SNPs (rs2076380, rs7270785, rs4811528, and rs6023526) related to the TGM2 gene and schizophrenia in a Chinese population [29]. Csomós et al. reported that TGM2 played an important role in neutrophil granulocyte differentiation and gene expression and argued that reduced expression of TGM2 in the NB4 model of acute promyelocytic leukemia might suppress effector functions of neutrophil granulocytes and attenuate the ATRA-induced inflammatory phenotype of DS [10]. According to Jambrovics et al., TGM2 expression is induced by all-trans retinoic acid in differentiated NB4 cells and nuclear factor kappa-light-chain (NF-kB) signaling network is responsible for driving pathogenic processes by initiating an inflammatory cascade through over-expression of interleukin 1 beta (IL-1β), numerous cytokines, and tumor necrosis factor alpha (TNF-α) [30]. A limitation of the present study was that the number of patients with DS was relatively small and further studies in a bigger population with DS are necessary to confirm the findings.
Conclusion
AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.
Abbreviations
APLAcute Promyelocytic Leukemia
ATRAAll Trans Retinoic Acid
ATOArsenic Trioxide
SNPSingle Nucleotide Polymorphism
CCL2CC motif Chemokine Ligand 2
ICAM-1Intercellular Adhesion Molecule-1
DSDifferentiation Syndrome
PETHEMAPrograma para el Tratamiento de Hemopatías Malignas
PCRPolymerase Chain Reaction
RFLPRestriction Fragment Length Polymorphism
ARMSThe Amplification-refractory Mutation System
LQTSLong QT Syndrome
TGM2Transglutaminase 2
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This study was supported by Hematology, Oncology, and Stem Cell Transplantation Research Center and Allied School of Medical Sciences of Tehran University of Medical Sciences.
Authors’ contributions
ZM: Acquired data, Drafted the manuscript. AO: Originated the study and substantively revised manuscript. BC: Acquired and interpreted data. GH: Performed statistical analysis, interpreted data. KAM: Design some part of the work. SAM: Design some part of the work. SHR: Made substantial contributions to the conception, design of the work. All authors have approved the submitted version and have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. The authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethics Code: IR.TUMS.SPH.REC.1397.269) and written informed consent was obtained from all participants.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. | ARSENIC TRIOXIDE, TRETINOIN | DrugsGivenReaction | CC BY | 33422029 | 19,136,194 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Adapting MRI as a clinical outcome measure for a facioscapulohumeral muscular dystrophy trial of prednisone and tacrolimus: case report.
BACKGROUND
Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. MRI short tau inversion recovery (STIR) sequences of patient muscles often show increased hyperintensity that is hypothesized to be associated with inflammation. This is supported by the presence of inflammatory changes on biopsies of STIR-positive muscles. We hypothesized that the STIR positivity would normalize with targeted immunosuppressive therapy.
METHODS
45-year-old male with FSHD type 1 was treated with 12 weeks of immunosuppressive therapy, tacrolimus and prednisone. Tacrolimus was treated to a goal serum trough of > 5 ng/mL and prednisone was tapered every month. Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12. The patient reported subjective worsening as reflected in quantitative strength exam. The MRI STIR signal was slightly increased from 0.02 to 0.03 of total muscle; while the T1 fat fraction was stable. Functional outcome measures also were stable.
CONCLUSIONS
Immunosuppressive therapy in refractive autoimmune myopathy in other contexts has been shown to reverse STIR signal hyperintensity, however this treatment did not reverse STIR signal in this patient with FSHD. In fact, STIR signal slightly increased throughout the treatment period. This is the first study of using MRI STIR and T1 fat fraction to follow treatment effect in FSHD. We find that STIR might not be a dynamic marker for suppressing inflammation in FSHD.
Background
Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle [1]. It is one of the most common muscular dystrophies that is the result of a toxic gain-of-function from de-repression of the DUX4 gene that is not normally expressed in skeletal muscle. The muscle histopathology underlying the disease is also variable, reflecting the patchy clinical involvement. Inflammation may be present in a subset of biopsies [2–4]. Given the intensity of the inflammation in some biopsies, pathologists have at times interpreted the histopathology as representing an immune-mediated disease such as polymyositis [2]. The inflammatory cells are endomysial, surrounding intact fibers, and often perivascular.
Multiple studies have assessed muscle MRI in patients with FSHD focusing on determining muscles to follow in a clinical trial either by imaging or muscle biopsy (looking for DUX4-downstream signature markers) [5–10]. MRI STIR sequences null the fat signal and highlight elevated free water signal. STIR hyperintensities indicate muscle edema, a feature associated with acute changes such as inflammation, trauma, metabolic derangements, or infection [11]. Two studies, Frisullo et al. and Tasca et al., performed biopsies on muscles with STIR hyperintensities and found 5/5 biopsies with endomysial CD8+ cells, perivascular CD4+ T-cells and CD68+ cells [12, 13]. Frisullo et al. found increased percentage of circulating CD8+pSTAT1+, CD8+T-bet+, and CD14+pSTAT1+ cells in 14/25 peripheral blood samples of FSHD patients with STIR hyperintensities, a significant increase when compared to FSHD patients without STIR hyperintensities and healthy controls. In the Seattle Wellstone FSHD study of 36 patients with MRI-guided biopsies, we found that MRI STIR positivity was associated with inflammation or active myopathy in ~ 70% of the muscle biopsies versus 25% of the STIR negative muscles [10]. A most recent paper by Dahlqvist et al. found that STIR-positive muscles indicating muscle inflammation were associated with faster muscle degradation [14]. Therefore, our hypothesis was that if STIR hyperintensities represent active inflammation, these abnormalities would normalize with targeted therapy.
We chose a combination of prednisone because of its fast onset and effect on both B and T cells; and tacrolimus for its effects on T cells. This multi-agent approach was selected given that a prior, open-label, 12-week trial of immunosuppression with prednisone (1.5 mg/kg/day) in eight FSHD patients failed to show improvement in muscle strength as assessed by manual muscle testing or maximum voluntary isometric contraction testing [15]. What was not evaluated in that study was MRI imaging which could certainly be more sensitive and specific than strength.
In refractory inflammatory myopathies, the use of a calcineurin inhibitor offers effective treatment [16]. STIR signal has been reported to be reversed in small case series of patients with inflammatory myositis [17] also in a case of TNF receptor-associated periodic syndrome [18]. We selected a three-month treatment duration similar to the duration of treatment trials for inflammatory myopathies to test our hypothesis.
Case presentation
The subject was a 45-year-old male with history of diabetes mellitus type 2 and FSHD type 1 (with clinical severity score of 2 and nine D4Z4 repeats) who first noticed symptoms at age 19, when he did 200 pull-ups as part of the Air Force Academy and thereafter lost the ability to do further pull ups. He also noticed lordosis while walking and attributed that to injury on an obstacle course. At the age 35, he realized that he could no longer set as a semi-pro volleyball player. At the age 39, after prolonged biking for a triathlon, he could no longer walk downstairs as he had problems stopping his forward progress. He then noticed that his arms got worse. He denied facial weakness but stated that his face gets tired and has been told that he never smiles. He denied problems with sucking on a straw or whistling. On exam, he demonstrated strong eyelid and lip closure, and cheek puff. Tongue and sternocleidomastoids were strong. His appendicular strength was intact, with the patient able to do deep knee bend but having a hard time walking on toes and heels. As part of the Seattle Wellstone study, an MRI showed STIR positivity in his left medial gastrocnemius and a biopsy of that muscle showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (Fig. 1a); also present was perivascular inflammation (Fig. 1b-c).
Fig. 1 Muscle histopathology of left medial gastrocnemius. Muscle histopathology showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (a); also present was perivascular inflammation (b-c). Courtesy of Dr. Rabi Tawil
After informed consent was obtained, the patient was treated for 3 months with an immunosuppressive regimen of tacrolimus (2.5–3 mg twice per day for goal trough 4 ng/dL) and prednisone (40 mg per day for the first month, 20 mg per day for the second month, and then 10 mg per day for the third month). Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12.
All MRI examinations were performed on a 3 T Philips Ingenia scanner. Sequences were acquired using flexible array coils to cover the pelvis down to the ankles in multiple stations (more to cover anatomy with thinner slices) with the following parameters in the axial acquisition plane: T1-weighted DIXON (Fast Field Echo [FFE] readout, four anatomical blocks [stations]: TE=1.35/2.58 ms, TR=shortest [example 4.12 ms], field-of-view [FOV] phase=300, FOV read=max, matrix=448 × 272, in-plane resolution=1.6 × 1.6 mm [thigh], 1.1 × 1.1 mm [calf], slice thickness=3 mm), STIR (three stations: TE=42 ms, TR=5277 ms, FOV phase=410, FOV read=max, matrix=448 × 260, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm, IR delay=220 ms), and T2-weighted DIXON (three stations: TE=97/97 ms [phase difference], TR=5570 ms, FOV phase=410, FOV read=max, matrix=448 × 272, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm). Total exam time was approximately 40 min equating to ~ 4 min per sequence (four stations T1 and three for STIR and T2 DIXON).
MRI data were imported into Slicer (http://www.slicer.org/, [19]) for processing. The algorithm developed creates a registered image set across the different image types. When you select a pixel within a region, for example a fatty replaced muscle compartment, across the registered images you get back a vector of voxel values, one value for each registered image at that spatial location. Since voxel values depend on the tissue type and on the MRI signal sequence, voxels with similar value vectors are likely to represent the same tissue type. The steps to select model classes and generate hard classified images is described in more detail below. Images underwent preprocessing steps: 1) stitching to join the separate series into a contiguous volume, 2) interpolation of all series to the highest resolution data (T1 DIXON), and 3) separate series intensity normalization and inhomogeneity correction. Next, data were exported for segmentation in MATLAB (Mathworks, Natick MA), with the time-points concatenated into a common block and then seeds were selected in the sum exams for the four primary classes of interest (fat, muscle, STIR+, bone). From these samples, gold-standard voxel value vectors were generated and the images classified by voxel vector similarity (least squared vector difference). To ensure that bone and sub-cutaneous fat were not included in volume measurements, both classes were expanded (digital dilation) by 5 and 4 pixels respectively. This has the practical result of removing the subcutaneous fat ring and ensuring that the bone mask is liberal enough to ensure that it is not being incorporated into muscle measures. As a last step, since bladder and vasculature appear as STIR bright features, these were removed the final segmentations by a rater blinded to time-point. This vector classification approach yielded excellent overlap between the multi-modality images for major tissue classes of interest (fat, muscle [normal-appearing], and STIR+ regions) as can be seen in Fig. 2. Summary volumes were computed for evaluating change with treatment.
Fig. 2 Vector Classification Example: From top, fat (T1 DIXON), water (T1 DIXON), water (T2 DIXON), and STIR images are shown from the same anatomical locations. Note the overlap between T2-weighted water measures and STIR+ signal. The vector segmentation overlaid on the STIR images follows, demonstrating the close correspondence between classes of air and subcutaneous tissue (green), bone (blue), muscle (red), fat (yellow), and STIR+ signal (pink). In the raw segmentation without overlay (bottom), black pixels are edited large vessels
There was no reversal of the abnormal STIR signal elevations seen at baseline by visual evaluation or by the volumes derived. Numerically, there was a slight increase in the fraction of muscle with STIR positivity from 0.02 at baseline to 0.03 at week 12 (Table 1). Data were expressed STIR/total at each time-point to account for weight changes. The stability of this biomarker and its potential to increase over the time-course can be seen in Fig. 3, with arrows demarcating areas of STIR+ features seen across the thigh and calf. Fat fraction assessed in bilateral legs showed no increase between baseline and at the end of the treatment period (12 weeks) with fat fraction at 0.27.
Table 1 MRI characteristics over 12 weeks of treatment
Baseline 6 weeks 12 weeks
STIR hyperintensity/muscle + STIR positivity 0.02 0.03 0.03
Fat fraction 0.27 0.28 0.27
Fig. 3 STIR and T1 MRI of lower extremity over the treatment period (6 and 12 weeks). The fat and water images derived from the T1 DIXON scan are shown at top and middle throughout the leg volumes across the study interval. In the bottom panel, regions with STIR+ signal are shown with arrows. The STIR+ signal persists at the two treatment time-points
Quantitative strength examination of the lower extremity by quantitative myometry showed mild decrease in bilateral knee flexion and ankle dorsiflexion strength (Table 2). Functional outcome measures showed no clinically significant changes (Table 2).
Table 2 Quantitative myometry (in Newtons) and functional outcome measures
Baseline 6 weeks 12 weeks
Knee flexion (right, N.) 22 13 13
Knee flexion (left) 62 40 36
Knee extension (right) 209 182 200
Knee extension (left) 227 218 209
Ankle dorsiflexion (right) 76 62 58
Ankle dorsiflexion (left) 89 62 36
6-min walk test (m) 600 580 596
Time up and go (sec) 5 5 5
Self-selected gait speed (sec) 4 3 3
Go 30 ft (sec) 4 4 4
Ascending stairs (sec) 2 2 2
Descending stairs (sec) 2 2 2
Sit to stand (sec) 1 1 1
The patient lost 9 kg during the study from a baseline weight of 104 kg. He reported no significant side-effect of the medications. Labs showed persistent hyperglycemia with hemoglobin A1c 6.6% at baseline and 8.8% at week 12. Tacrolimus trough levels were consistently therapeutic between 7.8 and 10.7 ng/mL. Renal function, potassium, magnesium, and phosphate levels were unaffected throughout the study.
Discussion and conclusions
Despite literature data (Tasca, Frisullo, Dahlqvist, our prior work [10, 12–14]) suggesting that STIR+ features may be primarily related to inflammation, we saw no change in signal intensity during a 12-week treatment trial with tacrolimus and prednisone. If we assume that STIR-positivity is primarily related to inflammation, then there may be a chance that the inflammation was not reversed with our regimen and that a more stringent regimen was required; however, we were using therapeutic doses of tacrolimus recommended for the treatment of inflammatory myopathies [16]; and therefore this is unlikely. Notable is a study [18] where complete resolution in STIR elevations did occur with equivalent immunosuppressive agents and time-course in a different muscle disease. However, this must be interpreted cautiously in our study, as while the patient clearly had inflammation on muscle biopsy prior to the study, we do not have a follow-up muscle biopsy to prove that our immunosuppressive regimen reduced the inflammation.
If we assume that our immunosuppressive regimen was therapeutic, then our findings support the idea that the STIR hyperintensity does not exclusively depend on active inflammation. This is a conclusion that we favor. While it could be envisioned that small inflammatory components would be modulated by our immunosuppressive regimen, the bulk of the abnormality remained stable and this perhaps reflects other pathological features such as edema, vasculature changes, fibrosis, and macroscopic features of cell death and reorganization. Such inflammatory mimicry in STIR signal is found in a broad range of diseases [20].
While we can debate the significance of the STIR signal, the immunosuppressive regimen of tacrolimus and prednisone did not improve strength as our patient subjectively reported worsened strength. This was borne out in the quantitative myometry. While it was unclear whether the changes in quantitative myometry were clinically significant, within error of measurement, or reflective of a volitional component, the patient’s strength measurements reflected his subjective experience during the study. There were other measurements that were stable throughout the study, such as distance walked in 6 min and the time in the time-up-and-go tests. Furthermore, his total T1 fat fraction of the leg muscles measured was unchanged suggesting that there was no progression in fatty replacement of muscle—a measure associated with increasing functional disability.
The inability of tacrolimus and prednisone to reverse the significant STIR hyperintensities on this patient’s muscle MRI, suggest that this regimen most likely will not succeed in reversing the STIR-positive signal in a larger study. We can also conclude that the short course of the immunosuppressive regimen of tacrolimus and prednisone did not improve the strength manifestations of FSHD. While it could always be argued that larger samples and/or longer studies are needed to generalize a single-subject result, the regimen and study design employed is not without risk. Our study shows the importance of objective outcome measures such as T1 fat fraction, representative of fibrofatty replacement, and functional outcome measure, as useful indices to infer the ever-hopeful treatment response.
Abbreviations
FSHDFacioscapulohumeral muscular dystrophy
MRIMagnetic resonance imaging
STIRshort tau inversion recovery
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank the Friends of FSH Research and Dr. Rabi Tawil for the histopathology slides.
Authors’ contributions
LHW, SJT, and SDF designed the study; edited and wrote the paper. LHW, SDF, and MB analyzed the data. LHW, SDF, and LMJ collected the data. All authors read and approve the manuscript.
Funding
Friends of FSH Research for funding the MRI, lab, outcome measure requisition, and the medications.
Study sponsorship: This work is supported by research grant from Friends of FSH Research.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Human Subjects Committee at the University of Washington, with written informed consent obtained.
An independent Safety Monitoring Committee consisting of one neurologist, a rheumatologist experienced in use of immunosuppressive medication, and a pharmacist reviewed safety data every 3 months throughout the trial.
Consent for publication
Written informed consent was obtained from the patient for publication of this Case Report. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Drs. Wang reports consultancy for Biogen. Drs. Friedman and Tapscott report consultancy for Fulcrum Therapeutics. | PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33422031 | 18,990,465 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Adapting MRI as a clinical outcome measure for a facioscapulohumeral muscular dystrophy trial of prednisone and tacrolimus: case report.
BACKGROUND
Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. MRI short tau inversion recovery (STIR) sequences of patient muscles often show increased hyperintensity that is hypothesized to be associated with inflammation. This is supported by the presence of inflammatory changes on biopsies of STIR-positive muscles. We hypothesized that the STIR positivity would normalize with targeted immunosuppressive therapy.
METHODS
45-year-old male with FSHD type 1 was treated with 12 weeks of immunosuppressive therapy, tacrolimus and prednisone. Tacrolimus was treated to a goal serum trough of > 5 ng/mL and prednisone was tapered every month. Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12. The patient reported subjective worsening as reflected in quantitative strength exam. The MRI STIR signal was slightly increased from 0.02 to 0.03 of total muscle; while the T1 fat fraction was stable. Functional outcome measures also were stable.
CONCLUSIONS
Immunosuppressive therapy in refractive autoimmune myopathy in other contexts has been shown to reverse STIR signal hyperintensity, however this treatment did not reverse STIR signal in this patient with FSHD. In fact, STIR signal slightly increased throughout the treatment period. This is the first study of using MRI STIR and T1 fat fraction to follow treatment effect in FSHD. We find that STIR might not be a dynamic marker for suppressing inflammation in FSHD.
Background
Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle [1]. It is one of the most common muscular dystrophies that is the result of a toxic gain-of-function from de-repression of the DUX4 gene that is not normally expressed in skeletal muscle. The muscle histopathology underlying the disease is also variable, reflecting the patchy clinical involvement. Inflammation may be present in a subset of biopsies [2–4]. Given the intensity of the inflammation in some biopsies, pathologists have at times interpreted the histopathology as representing an immune-mediated disease such as polymyositis [2]. The inflammatory cells are endomysial, surrounding intact fibers, and often perivascular.
Multiple studies have assessed muscle MRI in patients with FSHD focusing on determining muscles to follow in a clinical trial either by imaging or muscle biopsy (looking for DUX4-downstream signature markers) [5–10]. MRI STIR sequences null the fat signal and highlight elevated free water signal. STIR hyperintensities indicate muscle edema, a feature associated with acute changes such as inflammation, trauma, metabolic derangements, or infection [11]. Two studies, Frisullo et al. and Tasca et al., performed biopsies on muscles with STIR hyperintensities and found 5/5 biopsies with endomysial CD8+ cells, perivascular CD4+ T-cells and CD68+ cells [12, 13]. Frisullo et al. found increased percentage of circulating CD8+pSTAT1+, CD8+T-bet+, and CD14+pSTAT1+ cells in 14/25 peripheral blood samples of FSHD patients with STIR hyperintensities, a significant increase when compared to FSHD patients without STIR hyperintensities and healthy controls. In the Seattle Wellstone FSHD study of 36 patients with MRI-guided biopsies, we found that MRI STIR positivity was associated with inflammation or active myopathy in ~ 70% of the muscle biopsies versus 25% of the STIR negative muscles [10]. A most recent paper by Dahlqvist et al. found that STIR-positive muscles indicating muscle inflammation were associated with faster muscle degradation [14]. Therefore, our hypothesis was that if STIR hyperintensities represent active inflammation, these abnormalities would normalize with targeted therapy.
We chose a combination of prednisone because of its fast onset and effect on both B and T cells; and tacrolimus for its effects on T cells. This multi-agent approach was selected given that a prior, open-label, 12-week trial of immunosuppression with prednisone (1.5 mg/kg/day) in eight FSHD patients failed to show improvement in muscle strength as assessed by manual muscle testing or maximum voluntary isometric contraction testing [15]. What was not evaluated in that study was MRI imaging which could certainly be more sensitive and specific than strength.
In refractory inflammatory myopathies, the use of a calcineurin inhibitor offers effective treatment [16]. STIR signal has been reported to be reversed in small case series of patients with inflammatory myositis [17] also in a case of TNF receptor-associated periodic syndrome [18]. We selected a three-month treatment duration similar to the duration of treatment trials for inflammatory myopathies to test our hypothesis.
Case presentation
The subject was a 45-year-old male with history of diabetes mellitus type 2 and FSHD type 1 (with clinical severity score of 2 and nine D4Z4 repeats) who first noticed symptoms at age 19, when he did 200 pull-ups as part of the Air Force Academy and thereafter lost the ability to do further pull ups. He also noticed lordosis while walking and attributed that to injury on an obstacle course. At the age 35, he realized that he could no longer set as a semi-pro volleyball player. At the age 39, after prolonged biking for a triathlon, he could no longer walk downstairs as he had problems stopping his forward progress. He then noticed that his arms got worse. He denied facial weakness but stated that his face gets tired and has been told that he never smiles. He denied problems with sucking on a straw or whistling. On exam, he demonstrated strong eyelid and lip closure, and cheek puff. Tongue and sternocleidomastoids were strong. His appendicular strength was intact, with the patient able to do deep knee bend but having a hard time walking on toes and heels. As part of the Seattle Wellstone study, an MRI showed STIR positivity in his left medial gastrocnemius and a biopsy of that muscle showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (Fig. 1a); also present was perivascular inflammation (Fig. 1b-c).
Fig. 1 Muscle histopathology of left medial gastrocnemius. Muscle histopathology showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (a); also present was perivascular inflammation (b-c). Courtesy of Dr. Rabi Tawil
After informed consent was obtained, the patient was treated for 3 months with an immunosuppressive regimen of tacrolimus (2.5–3 mg twice per day for goal trough 4 ng/dL) and prednisone (40 mg per day for the first month, 20 mg per day for the second month, and then 10 mg per day for the third month). Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12.
All MRI examinations were performed on a 3 T Philips Ingenia scanner. Sequences were acquired using flexible array coils to cover the pelvis down to the ankles in multiple stations (more to cover anatomy with thinner slices) with the following parameters in the axial acquisition plane: T1-weighted DIXON (Fast Field Echo [FFE] readout, four anatomical blocks [stations]: TE=1.35/2.58 ms, TR=shortest [example 4.12 ms], field-of-view [FOV] phase=300, FOV read=max, matrix=448 × 272, in-plane resolution=1.6 × 1.6 mm [thigh], 1.1 × 1.1 mm [calf], slice thickness=3 mm), STIR (three stations: TE=42 ms, TR=5277 ms, FOV phase=410, FOV read=max, matrix=448 × 260, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm, IR delay=220 ms), and T2-weighted DIXON (three stations: TE=97/97 ms [phase difference], TR=5570 ms, FOV phase=410, FOV read=max, matrix=448 × 272, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm). Total exam time was approximately 40 min equating to ~ 4 min per sequence (four stations T1 and three for STIR and T2 DIXON).
MRI data were imported into Slicer (http://www.slicer.org/, [19]) for processing. The algorithm developed creates a registered image set across the different image types. When you select a pixel within a region, for example a fatty replaced muscle compartment, across the registered images you get back a vector of voxel values, one value for each registered image at that spatial location. Since voxel values depend on the tissue type and on the MRI signal sequence, voxels with similar value vectors are likely to represent the same tissue type. The steps to select model classes and generate hard classified images is described in more detail below. Images underwent preprocessing steps: 1) stitching to join the separate series into a contiguous volume, 2) interpolation of all series to the highest resolution data (T1 DIXON), and 3) separate series intensity normalization and inhomogeneity correction. Next, data were exported for segmentation in MATLAB (Mathworks, Natick MA), with the time-points concatenated into a common block and then seeds were selected in the sum exams for the four primary classes of interest (fat, muscle, STIR+, bone). From these samples, gold-standard voxel value vectors were generated and the images classified by voxel vector similarity (least squared vector difference). To ensure that bone and sub-cutaneous fat were not included in volume measurements, both classes were expanded (digital dilation) by 5 and 4 pixels respectively. This has the practical result of removing the subcutaneous fat ring and ensuring that the bone mask is liberal enough to ensure that it is not being incorporated into muscle measures. As a last step, since bladder and vasculature appear as STIR bright features, these were removed the final segmentations by a rater blinded to time-point. This vector classification approach yielded excellent overlap between the multi-modality images for major tissue classes of interest (fat, muscle [normal-appearing], and STIR+ regions) as can be seen in Fig. 2. Summary volumes were computed for evaluating change with treatment.
Fig. 2 Vector Classification Example: From top, fat (T1 DIXON), water (T1 DIXON), water (T2 DIXON), and STIR images are shown from the same anatomical locations. Note the overlap between T2-weighted water measures and STIR+ signal. The vector segmentation overlaid on the STIR images follows, demonstrating the close correspondence between classes of air and subcutaneous tissue (green), bone (blue), muscle (red), fat (yellow), and STIR+ signal (pink). In the raw segmentation without overlay (bottom), black pixels are edited large vessels
There was no reversal of the abnormal STIR signal elevations seen at baseline by visual evaluation or by the volumes derived. Numerically, there was a slight increase in the fraction of muscle with STIR positivity from 0.02 at baseline to 0.03 at week 12 (Table 1). Data were expressed STIR/total at each time-point to account for weight changes. The stability of this biomarker and its potential to increase over the time-course can be seen in Fig. 3, with arrows demarcating areas of STIR+ features seen across the thigh and calf. Fat fraction assessed in bilateral legs showed no increase between baseline and at the end of the treatment period (12 weeks) with fat fraction at 0.27.
Table 1 MRI characteristics over 12 weeks of treatment
Baseline 6 weeks 12 weeks
STIR hyperintensity/muscle + STIR positivity 0.02 0.03 0.03
Fat fraction 0.27 0.28 0.27
Fig. 3 STIR and T1 MRI of lower extremity over the treatment period (6 and 12 weeks). The fat and water images derived from the T1 DIXON scan are shown at top and middle throughout the leg volumes across the study interval. In the bottom panel, regions with STIR+ signal are shown with arrows. The STIR+ signal persists at the two treatment time-points
Quantitative strength examination of the lower extremity by quantitative myometry showed mild decrease in bilateral knee flexion and ankle dorsiflexion strength (Table 2). Functional outcome measures showed no clinically significant changes (Table 2).
Table 2 Quantitative myometry (in Newtons) and functional outcome measures
Baseline 6 weeks 12 weeks
Knee flexion (right, N.) 22 13 13
Knee flexion (left) 62 40 36
Knee extension (right) 209 182 200
Knee extension (left) 227 218 209
Ankle dorsiflexion (right) 76 62 58
Ankle dorsiflexion (left) 89 62 36
6-min walk test (m) 600 580 596
Time up and go (sec) 5 5 5
Self-selected gait speed (sec) 4 3 3
Go 30 ft (sec) 4 4 4
Ascending stairs (sec) 2 2 2
Descending stairs (sec) 2 2 2
Sit to stand (sec) 1 1 1
The patient lost 9 kg during the study from a baseline weight of 104 kg. He reported no significant side-effect of the medications. Labs showed persistent hyperglycemia with hemoglobin A1c 6.6% at baseline and 8.8% at week 12. Tacrolimus trough levels were consistently therapeutic between 7.8 and 10.7 ng/mL. Renal function, potassium, magnesium, and phosphate levels were unaffected throughout the study.
Discussion and conclusions
Despite literature data (Tasca, Frisullo, Dahlqvist, our prior work [10, 12–14]) suggesting that STIR+ features may be primarily related to inflammation, we saw no change in signal intensity during a 12-week treatment trial with tacrolimus and prednisone. If we assume that STIR-positivity is primarily related to inflammation, then there may be a chance that the inflammation was not reversed with our regimen and that a more stringent regimen was required; however, we were using therapeutic doses of tacrolimus recommended for the treatment of inflammatory myopathies [16]; and therefore this is unlikely. Notable is a study [18] where complete resolution in STIR elevations did occur with equivalent immunosuppressive agents and time-course in a different muscle disease. However, this must be interpreted cautiously in our study, as while the patient clearly had inflammation on muscle biopsy prior to the study, we do not have a follow-up muscle biopsy to prove that our immunosuppressive regimen reduced the inflammation.
If we assume that our immunosuppressive regimen was therapeutic, then our findings support the idea that the STIR hyperintensity does not exclusively depend on active inflammation. This is a conclusion that we favor. While it could be envisioned that small inflammatory components would be modulated by our immunosuppressive regimen, the bulk of the abnormality remained stable and this perhaps reflects other pathological features such as edema, vasculature changes, fibrosis, and macroscopic features of cell death and reorganization. Such inflammatory mimicry in STIR signal is found in a broad range of diseases [20].
While we can debate the significance of the STIR signal, the immunosuppressive regimen of tacrolimus and prednisone did not improve strength as our patient subjectively reported worsened strength. This was borne out in the quantitative myometry. While it was unclear whether the changes in quantitative myometry were clinically significant, within error of measurement, or reflective of a volitional component, the patient’s strength measurements reflected his subjective experience during the study. There were other measurements that were stable throughout the study, such as distance walked in 6 min and the time in the time-up-and-go tests. Furthermore, his total T1 fat fraction of the leg muscles measured was unchanged suggesting that there was no progression in fatty replacement of muscle—a measure associated with increasing functional disability.
The inability of tacrolimus and prednisone to reverse the significant STIR hyperintensities on this patient’s muscle MRI, suggest that this regimen most likely will not succeed in reversing the STIR-positive signal in a larger study. We can also conclude that the short course of the immunosuppressive regimen of tacrolimus and prednisone did not improve the strength manifestations of FSHD. While it could always be argued that larger samples and/or longer studies are needed to generalize a single-subject result, the regimen and study design employed is not without risk. Our study shows the importance of objective outcome measures such as T1 fat fraction, representative of fibrofatty replacement, and functional outcome measure, as useful indices to infer the ever-hopeful treatment response.
Abbreviations
FSHDFacioscapulohumeral muscular dystrophy
MRIMagnetic resonance imaging
STIRshort tau inversion recovery
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank the Friends of FSH Research and Dr. Rabi Tawil for the histopathology slides.
Authors’ contributions
LHW, SJT, and SDF designed the study; edited and wrote the paper. LHW, SDF, and MB analyzed the data. LHW, SDF, and LMJ collected the data. All authors read and approve the manuscript.
Funding
Friends of FSH Research for funding the MRI, lab, outcome measure requisition, and the medications.
Study sponsorship: This work is supported by research grant from Friends of FSH Research.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Human Subjects Committee at the University of Washington, with written informed consent obtained.
An independent Safety Monitoring Committee consisting of one neurologist, a rheumatologist experienced in use of immunosuppressive medication, and a pharmacist reviewed safety data every 3 months throughout the trial.
Consent for publication
Written informed consent was obtained from the patient for publication of this Case Report. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Drs. Wang reports consultancy for Biogen. Drs. Friedman and Tapscott report consultancy for Fulcrum Therapeutics. | PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33422031 | 19,059,262 | 2021-01-09 |
What is the weight of the patient? | Adapting MRI as a clinical outcome measure for a facioscapulohumeral muscular dystrophy trial of prednisone and tacrolimus: case report.
BACKGROUND
Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. MRI short tau inversion recovery (STIR) sequences of patient muscles often show increased hyperintensity that is hypothesized to be associated with inflammation. This is supported by the presence of inflammatory changes on biopsies of STIR-positive muscles. We hypothesized that the STIR positivity would normalize with targeted immunosuppressive therapy.
METHODS
45-year-old male with FSHD type 1 was treated with 12 weeks of immunosuppressive therapy, tacrolimus and prednisone. Tacrolimus was treated to a goal serum trough of > 5 ng/mL and prednisone was tapered every month. Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12. The patient reported subjective worsening as reflected in quantitative strength exam. The MRI STIR signal was slightly increased from 0.02 to 0.03 of total muscle; while the T1 fat fraction was stable. Functional outcome measures also were stable.
CONCLUSIONS
Immunosuppressive therapy in refractive autoimmune myopathy in other contexts has been shown to reverse STIR signal hyperintensity, however this treatment did not reverse STIR signal in this patient with FSHD. In fact, STIR signal slightly increased throughout the treatment period. This is the first study of using MRI STIR and T1 fat fraction to follow treatment effect in FSHD. We find that STIR might not be a dynamic marker for suppressing inflammation in FSHD.
Background
Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle [1]. It is one of the most common muscular dystrophies that is the result of a toxic gain-of-function from de-repression of the DUX4 gene that is not normally expressed in skeletal muscle. The muscle histopathology underlying the disease is also variable, reflecting the patchy clinical involvement. Inflammation may be present in a subset of biopsies [2–4]. Given the intensity of the inflammation in some biopsies, pathologists have at times interpreted the histopathology as representing an immune-mediated disease such as polymyositis [2]. The inflammatory cells are endomysial, surrounding intact fibers, and often perivascular.
Multiple studies have assessed muscle MRI in patients with FSHD focusing on determining muscles to follow in a clinical trial either by imaging or muscle biopsy (looking for DUX4-downstream signature markers) [5–10]. MRI STIR sequences null the fat signal and highlight elevated free water signal. STIR hyperintensities indicate muscle edema, a feature associated with acute changes such as inflammation, trauma, metabolic derangements, or infection [11]. Two studies, Frisullo et al. and Tasca et al., performed biopsies on muscles with STIR hyperintensities and found 5/5 biopsies with endomysial CD8+ cells, perivascular CD4+ T-cells and CD68+ cells [12, 13]. Frisullo et al. found increased percentage of circulating CD8+pSTAT1+, CD8+T-bet+, and CD14+pSTAT1+ cells in 14/25 peripheral blood samples of FSHD patients with STIR hyperintensities, a significant increase when compared to FSHD patients without STIR hyperintensities and healthy controls. In the Seattle Wellstone FSHD study of 36 patients with MRI-guided biopsies, we found that MRI STIR positivity was associated with inflammation or active myopathy in ~ 70% of the muscle biopsies versus 25% of the STIR negative muscles [10]. A most recent paper by Dahlqvist et al. found that STIR-positive muscles indicating muscle inflammation were associated with faster muscle degradation [14]. Therefore, our hypothesis was that if STIR hyperintensities represent active inflammation, these abnormalities would normalize with targeted therapy.
We chose a combination of prednisone because of its fast onset and effect on both B and T cells; and tacrolimus for its effects on T cells. This multi-agent approach was selected given that a prior, open-label, 12-week trial of immunosuppression with prednisone (1.5 mg/kg/day) in eight FSHD patients failed to show improvement in muscle strength as assessed by manual muscle testing or maximum voluntary isometric contraction testing [15]. What was not evaluated in that study was MRI imaging which could certainly be more sensitive and specific than strength.
In refractory inflammatory myopathies, the use of a calcineurin inhibitor offers effective treatment [16]. STIR signal has been reported to be reversed in small case series of patients with inflammatory myositis [17] also in a case of TNF receptor-associated periodic syndrome [18]. We selected a three-month treatment duration similar to the duration of treatment trials for inflammatory myopathies to test our hypothesis.
Case presentation
The subject was a 45-year-old male with history of diabetes mellitus type 2 and FSHD type 1 (with clinical severity score of 2 and nine D4Z4 repeats) who first noticed symptoms at age 19, when he did 200 pull-ups as part of the Air Force Academy and thereafter lost the ability to do further pull ups. He also noticed lordosis while walking and attributed that to injury on an obstacle course. At the age 35, he realized that he could no longer set as a semi-pro volleyball player. At the age 39, after prolonged biking for a triathlon, he could no longer walk downstairs as he had problems stopping his forward progress. He then noticed that his arms got worse. He denied facial weakness but stated that his face gets tired and has been told that he never smiles. He denied problems with sucking on a straw or whistling. On exam, he demonstrated strong eyelid and lip closure, and cheek puff. Tongue and sternocleidomastoids were strong. His appendicular strength was intact, with the patient able to do deep knee bend but having a hard time walking on toes and heels. As part of the Seattle Wellstone study, an MRI showed STIR positivity in his left medial gastrocnemius and a biopsy of that muscle showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (Fig. 1a); also present was perivascular inflammation (Fig. 1b-c).
Fig. 1 Muscle histopathology of left medial gastrocnemius. Muscle histopathology showed a chronic myopathy with severe myofiber size variability, necrosis, and increased endomysial inflammation (a); also present was perivascular inflammation (b-c). Courtesy of Dr. Rabi Tawil
After informed consent was obtained, the patient was treated for 3 months with an immunosuppressive regimen of tacrolimus (2.5–3 mg twice per day for goal trough 4 ng/dL) and prednisone (40 mg per day for the first month, 20 mg per day for the second month, and then 10 mg per day for the third month). Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12.
All MRI examinations were performed on a 3 T Philips Ingenia scanner. Sequences were acquired using flexible array coils to cover the pelvis down to the ankles in multiple stations (more to cover anatomy with thinner slices) with the following parameters in the axial acquisition plane: T1-weighted DIXON (Fast Field Echo [FFE] readout, four anatomical blocks [stations]: TE=1.35/2.58 ms, TR=shortest [example 4.12 ms], field-of-view [FOV] phase=300, FOV read=max, matrix=448 × 272, in-plane resolution=1.6 × 1.6 mm [thigh], 1.1 × 1.1 mm [calf], slice thickness=3 mm), STIR (three stations: TE=42 ms, TR=5277 ms, FOV phase=410, FOV read=max, matrix=448 × 260, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm, IR delay=220 ms), and T2-weighted DIXON (three stations: TE=97/97 ms [phase difference], TR=5570 ms, FOV phase=410, FOV read=max, matrix=448 × 272, in-plane resolution=1.1 × 1.1 mm, slice thickness=9 mm). Total exam time was approximately 40 min equating to ~ 4 min per sequence (four stations T1 and three for STIR and T2 DIXON).
MRI data were imported into Slicer (http://www.slicer.org/, [19]) for processing. The algorithm developed creates a registered image set across the different image types. When you select a pixel within a region, for example a fatty replaced muscle compartment, across the registered images you get back a vector of voxel values, one value for each registered image at that spatial location. Since voxel values depend on the tissue type and on the MRI signal sequence, voxels with similar value vectors are likely to represent the same tissue type. The steps to select model classes and generate hard classified images is described in more detail below. Images underwent preprocessing steps: 1) stitching to join the separate series into a contiguous volume, 2) interpolation of all series to the highest resolution data (T1 DIXON), and 3) separate series intensity normalization and inhomogeneity correction. Next, data were exported for segmentation in MATLAB (Mathworks, Natick MA), with the time-points concatenated into a common block and then seeds were selected in the sum exams for the four primary classes of interest (fat, muscle, STIR+, bone). From these samples, gold-standard voxel value vectors were generated and the images classified by voxel vector similarity (least squared vector difference). To ensure that bone and sub-cutaneous fat were not included in volume measurements, both classes were expanded (digital dilation) by 5 and 4 pixels respectively. This has the practical result of removing the subcutaneous fat ring and ensuring that the bone mask is liberal enough to ensure that it is not being incorporated into muscle measures. As a last step, since bladder and vasculature appear as STIR bright features, these were removed the final segmentations by a rater blinded to time-point. This vector classification approach yielded excellent overlap between the multi-modality images for major tissue classes of interest (fat, muscle [normal-appearing], and STIR+ regions) as can be seen in Fig. 2. Summary volumes were computed for evaluating change with treatment.
Fig. 2 Vector Classification Example: From top, fat (T1 DIXON), water (T1 DIXON), water (T2 DIXON), and STIR images are shown from the same anatomical locations. Note the overlap between T2-weighted water measures and STIR+ signal. The vector segmentation overlaid on the STIR images follows, demonstrating the close correspondence between classes of air and subcutaneous tissue (green), bone (blue), muscle (red), fat (yellow), and STIR+ signal (pink). In the raw segmentation without overlay (bottom), black pixels are edited large vessels
There was no reversal of the abnormal STIR signal elevations seen at baseline by visual evaluation or by the volumes derived. Numerically, there was a slight increase in the fraction of muscle with STIR positivity from 0.02 at baseline to 0.03 at week 12 (Table 1). Data were expressed STIR/total at each time-point to account for weight changes. The stability of this biomarker and its potential to increase over the time-course can be seen in Fig. 3, with arrows demarcating areas of STIR+ features seen across the thigh and calf. Fat fraction assessed in bilateral legs showed no increase between baseline and at the end of the treatment period (12 weeks) with fat fraction at 0.27.
Table 1 MRI characteristics over 12 weeks of treatment
Baseline 6 weeks 12 weeks
STIR hyperintensity/muscle + STIR positivity 0.02 0.03 0.03
Fat fraction 0.27 0.28 0.27
Fig. 3 STIR and T1 MRI of lower extremity over the treatment period (6 and 12 weeks). The fat and water images derived from the T1 DIXON scan are shown at top and middle throughout the leg volumes across the study interval. In the bottom panel, regions with STIR+ signal are shown with arrows. The STIR+ signal persists at the two treatment time-points
Quantitative strength examination of the lower extremity by quantitative myometry showed mild decrease in bilateral knee flexion and ankle dorsiflexion strength (Table 2). Functional outcome measures showed no clinically significant changes (Table 2).
Table 2 Quantitative myometry (in Newtons) and functional outcome measures
Baseline 6 weeks 12 weeks
Knee flexion (right, N.) 22 13 13
Knee flexion (left) 62 40 36
Knee extension (right) 209 182 200
Knee extension (left) 227 218 209
Ankle dorsiflexion (right) 76 62 58
Ankle dorsiflexion (left) 89 62 36
6-min walk test (m) 600 580 596
Time up and go (sec) 5 5 5
Self-selected gait speed (sec) 4 3 3
Go 30 ft (sec) 4 4 4
Ascending stairs (sec) 2 2 2
Descending stairs (sec) 2 2 2
Sit to stand (sec) 1 1 1
The patient lost 9 kg during the study from a baseline weight of 104 kg. He reported no significant side-effect of the medications. Labs showed persistent hyperglycemia with hemoglobin A1c 6.6% at baseline and 8.8% at week 12. Tacrolimus trough levels were consistently therapeutic between 7.8 and 10.7 ng/mL. Renal function, potassium, magnesium, and phosphate levels were unaffected throughout the study.
Discussion and conclusions
Despite literature data (Tasca, Frisullo, Dahlqvist, our prior work [10, 12–14]) suggesting that STIR+ features may be primarily related to inflammation, we saw no change in signal intensity during a 12-week treatment trial with tacrolimus and prednisone. If we assume that STIR-positivity is primarily related to inflammation, then there may be a chance that the inflammation was not reversed with our regimen and that a more stringent regimen was required; however, we were using therapeutic doses of tacrolimus recommended for the treatment of inflammatory myopathies [16]; and therefore this is unlikely. Notable is a study [18] where complete resolution in STIR elevations did occur with equivalent immunosuppressive agents and time-course in a different muscle disease. However, this must be interpreted cautiously in our study, as while the patient clearly had inflammation on muscle biopsy prior to the study, we do not have a follow-up muscle biopsy to prove that our immunosuppressive regimen reduced the inflammation.
If we assume that our immunosuppressive regimen was therapeutic, then our findings support the idea that the STIR hyperintensity does not exclusively depend on active inflammation. This is a conclusion that we favor. While it could be envisioned that small inflammatory components would be modulated by our immunosuppressive regimen, the bulk of the abnormality remained stable and this perhaps reflects other pathological features such as edema, vasculature changes, fibrosis, and macroscopic features of cell death and reorganization. Such inflammatory mimicry in STIR signal is found in a broad range of diseases [20].
While we can debate the significance of the STIR signal, the immunosuppressive regimen of tacrolimus and prednisone did not improve strength as our patient subjectively reported worsened strength. This was borne out in the quantitative myometry. While it was unclear whether the changes in quantitative myometry were clinically significant, within error of measurement, or reflective of a volitional component, the patient’s strength measurements reflected his subjective experience during the study. There were other measurements that were stable throughout the study, such as distance walked in 6 min and the time in the time-up-and-go tests. Furthermore, his total T1 fat fraction of the leg muscles measured was unchanged suggesting that there was no progression in fatty replacement of muscle—a measure associated with increasing functional disability.
The inability of tacrolimus and prednisone to reverse the significant STIR hyperintensities on this patient’s muscle MRI, suggest that this regimen most likely will not succeed in reversing the STIR-positive signal in a larger study. We can also conclude that the short course of the immunosuppressive regimen of tacrolimus and prednisone did not improve the strength manifestations of FSHD. While it could always be argued that larger samples and/or longer studies are needed to generalize a single-subject result, the regimen and study design employed is not without risk. Our study shows the importance of objective outcome measures such as T1 fat fraction, representative of fibrofatty replacement, and functional outcome measure, as useful indices to infer the ever-hopeful treatment response.
Abbreviations
FSHDFacioscapulohumeral muscular dystrophy
MRIMagnetic resonance imaging
STIRshort tau inversion recovery
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank the Friends of FSH Research and Dr. Rabi Tawil for the histopathology slides.
Authors’ contributions
LHW, SJT, and SDF designed the study; edited and wrote the paper. LHW, SDF, and MB analyzed the data. LHW, SDF, and LMJ collected the data. All authors read and approve the manuscript.
Funding
Friends of FSH Research for funding the MRI, lab, outcome measure requisition, and the medications.
Study sponsorship: This work is supported by research grant from Friends of FSH Research.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Human Subjects Committee at the University of Washington, with written informed consent obtained.
An independent Safety Monitoring Committee consisting of one neurologist, a rheumatologist experienced in use of immunosuppressive medication, and a pharmacist reviewed safety data every 3 months throughout the trial.
Consent for publication
Written informed consent was obtained from the patient for publication of this Case Report. A copy of the written consent is available for review by the Editor of this journal.
Competing interests
Drs. Wang reports consultancy for Biogen. Drs. Friedman and Tapscott report consultancy for Fulcrum Therapeutics. | 104 kg. | Weight | CC BY | 33422031 | 18,990,465 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukopenia'. | Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review.
BACKGROUND
Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).
METHODS
We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.
CONCLUSIONS
Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
Background
The DNA mismatch repair (MMR) pathway functions to recognize and repair base pair mismatches that arise during DNA replication and recombination and plays a key role in maintaining genomic stability. Defects in mismatch repair (dMMR) account for approximately 15% of colorectal cancer (CRC) [1]. Approximately 3% of CRC are associated with Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer (HNPCC), an autosomal dominant disease and the most common inherited form of CRC arising from monoallelic germline mutation in MLH1, MSH2, MSH6, or PMS2 [2]. Another hereditary syndrome associated with dMMR is constitutional mismatch repair deficiency (CMMRD) syndrome, which is a rare autosomal recessive cancer-predisposing syndrome resulting from bi-allelic germline mutations in MMR genes [3].
National Comprehensive Cancer Network (NCCN) guideline now recommends all patients diagnosed with CRC to undergo MMR and microsatellite instability (MSI) testing to screen for inherited CRC, which is instrumental in identifying Lynch and CMMRD syndromes [4]. Proper diagnosis of these inherited cancer syndromes is necessary for optimal clinical management, including the decision to perform surgery and appropriate adjuvant chemotherapy [2, 5, 6]. However, tumor heterogeneity could contribute to inconsistent MMR-IHC or MSI results, which delays the diagnosis and affects the treatment outcomes [7, 8]. Herein, we report a patient with CMMRD and metastatic CRC resulting from bi-allelic germline MSH6 mutation who had heterogeneous MMR-IHC with high tumor mutations burden (TMB-H) but microsatellite stable (MSS) status that led to his complicated response to immune checkpoint inhibitor (ICI) therapy. We have prepared this manuscript in accordance with the CARE guidelines.
Case presentation
In November 2016, a 32-year-old male presented with a chief complaint of hematochezia for 2 years was diagnosed with early-onset colon cancer with peritoneal metastasis (T4bN1M1). Abdominal computed tomography (CT) scans showed a mass in the splenic flexure of the colon with presence of multiple peritoneal nodules (Fig. 1). Additionally, histopathology examination of the tissue biopsy revealed poorly- to moderately-differentiated adenocarcinoma with mucinous features. Palliative first-line FOLFOXIRI regimen (D1: 5-fluorouracil 2.8 g/m2 5g civ46 + oxaliplatin 85 mg/m2 150mg + irinotecan 165 mg/m2 300mg q14d) was administered for a total of 6 cycles achieving stable disease (SD) (Fig. 1). On March 2017, laparotomy and subtotal colectomy was performed with no postoperative complications and confirmed the pathological stage of pT4bN1a. Immunohistochemistry (MMR-IHC) of different sections of formalin-fixed paraffin-embedded (FFPE) blocks of the surgically-removed tumor demonstrated heterogeneity in MMR status, with one section demonstrating complete loss of MSH6 expression and evaluated as MMR deficient (dMMR) (Fig. 2a), while another section demonstrating clonal loss of MSH6 (Fig. 2b, MSH6-1X), but still evaluated as MMR proficient (pMMR) due to moderate staining in some clones (Fig. 2b). However, the MSI status of both blocks was determined as MSS by polymerase chain reaction (PCR)–based analysis (Fig. S1). To further understand the biology of this heterogeneity, two tissue specimens used for MMR-IHC and an additional plasma sample were submitted for comprehensive targeted sequencing with a 520-gene panel (OncoScreen Plus, Burning Rock Biotech). Table S1 summarizes the sequencing results. The tumor mutation burden (TMB) status of all his samples was assessed to be TMB-H. Careful inspection of the mutation profile revealed that the pMMR tissue sample and blood sample had similar mutation profile and different from the dMMR sample. Despite the variability in mutation profile between the pMMR and dMMR tissue samples, a homozygous missense mutation in the exon 5 of MSH6 gene, c.3226C > T (p.R1076C), was consistently detected in both tissue samples and blood sample. In addition to the consistent wild-type status for HRAS, KRAS, and NRAS, a SMAD4 R361H was also consistently detected in all his samples. Homozygous germline mutation status of MSH6 R1076C was also confirmed using lymphocyte-derived genomic DNA analysis (Fig. S2A). Further investigations of his family history revealed that his paternal grandfather and maternal grandmother had stomach cancer and endometrial cancer, respectively (Fig. S2B, I.1 and I.2). He was born from fourth-degree consanguineous parents. His back and abdomen are scattered with multiple café-au-lait macula and neurofibromas with unknown age of occurrence. His daughters were born with blue birthmark. Moreover, genetic testing of his immediate family members revealed heterozygous MSH6 R1076C, strongly indicating an autosomal recessive inheritance pattern (Fig. S2B). Based on his clinical and genetic data, he was additionally diagnosed with late-onset CMMRD.
Fig. 1 Summary of the treatment received by the patient, including the best objective response (OR) and progression-free survival (PFS) in each line of treatment. Abdominal computed tomography (CT) scans are also provided. Red arrows indicate the primary lesions
Fig. 2 Immunohistochemical staining of MSH6, MSH2, MLH1, and PMS2. One section of the surgical tissue sample was evaluated as (a) MMR deficient (dMMR) and the other as (b) MMR proficient (pMMR). Hematoxylin Eosin staining, MSH6, MSH2, MLH1 and PMS2 were collected at 4X magnification, unless otherwise indicated (i.e. magnification of 1X for MSH6 in the second panel on top)
Since post-colectomy, he was administered with FOLFOX and cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + cetuximab 500 mg/kg q14d) for 8 cycles achieving SD. He experienced leukopenia multiple times throughout the treatment process. In March 2018, disease recurrence was suspected after a review of abdominal CT revealed a ring-shaped 50x31mm mass in the peritoneal folds of the anterior pelvic cavity. After reviewing literatures from MEDLINE, we found promising evidence of clinical response to ICI treatment in patients with CMMRD as summarized in Table S2 [9–13]. He was enrolled in a clinical trial for anti-PD-L1 monoclonal antibody CS1001–101 administered at 1200 mg in four-cycle regimen (NCT03744403). The treatment was well tolerated. Despite an unresponsive disease, he chose to remain on the treatment for another 4 cycles until confirmation of disease progression as per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. After immunotherapy was terminated, he was administered with FOLFOXIRI + cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + irinotecan 120 mg/m2 + cetuximab 500 mg/kg q14d) from November 2018 to October 2019 until progression. After the failure of one cycle ipilimumab (D1: 50 mg) and pembrolizumab (D1: 200 mg), pembrolizumab plus regorafenib (D1: pembrolizumab 200 mg, D1-D21 regorafenib 80 mg q21d) was administered in the next cycle (November 2019) considering the CMMRD and MSS status of the tumor. After 1 week of combination therapy, regorafenib was suspended due to grade 3 rash. Surprisingly, his clinical symptoms of CRC including abdominal pain were markedly relieved, which led to a remarkable improvement in his ECOG PS from 3 to 0. Serum tumor marker CEA also decreased from 13.18 ng/ml to 4.04 ng/ml within 1 month of combination therapy. After the rash resolved, he resumed regorafenib at a reduced dose of 40 mg qd without any chief complaint. His disease remains stable for 6 months as of the last follow-up on May 25, 2020.
Discussion
Due to the rarity of CMMRD, early diagnosis is challenging particularly in patients with no family history of cancer and delayed onset of malignancies. In our case, CMMRD was incidentally diagnosed due to the detection of bi-allelic germline MSH6 R1076C mutation by targeted sequencing. Targeted sequencing allowed the detection of the homozygous mutation which then led to further discovery of the presence of dermatological manifestations (i.e. café-au-lait spots and neurofibromas), family history of cancer, mutation carrier status of immediate family members, and consanguinity of the parents that all together helped in forming a conclusive diagnosis. His family has been appropriately counseled regarding their increased risk of developing cancer. Interestingly, our patient with CMMRD had TMB-H but failed to respond to anti-PD-L1 monotherapy with CS1001–101 and combined therapy of anti-PD-1 and anti-CTLA-4 monoclonal antibodies, which may be due to tumor heterogeneity and MSS status. However, the addition of an anti-VEGFR2 multi-kinase inhibitor regorafenib to the anti-PD-1 therapy was clinically effective for our patient.
CMMRD is associated with poor prognosis and typically manifested as childhood cancers including brain tumors, hematological malignancies, and gastrointestinal tumors [3, 5]. Missense R1076C mutation of MSH6 gene is located on the ATPase domain and has been evaluated as likely pathogenic in ClinVar database (Variation ID: 89357) with multiple evidence associating this mutation with HNPCC and hereditary cancer-predisposing syndrome. Bi-allelic germline MSH6 R1076C mutation was also reported in a 45-year-old patient diagnosed with CRC [14]. The phenotype presentation in the patients with mono-allelic or bi-allelic MSH6 R1076C seemed to be milder compared with those with bi-allelic mutations in other MMR genes [14–16]. Delayed age of onset has generally been observed for MSH6 mutation carriers as compared to MSH2 or MLH1 mutants [17–19]. Moreover, MSH6 missense mutation carriers were more likely to develop CRC than those with truncating mutations [18]. Consistently, bi-allelic germline MSH6 R1076C mutation of our patient led to the development of CRC in the third decade of life but without any hematological malignancy or brain tumor. According to the report by Plaschke and colleagues, the hypomorphic nature of MSH6 missense mutation might only bring about partial abolishment of its protein function [15]. This hypomorphic mutation might also explain the intratumor genetic heterogeneity demonstrated by heterogeneous MMR-IHC status and distinct mutation profile of the two tumor block samples from our patient.
Conventionally, the complete absence of MSH6 nuclear staining in both tumor and normal cells of the colonic mucosa is typically observed in patients with bi-allelic MSH6 mutation [14–16]. However, MSI is not always present among MSH6 mutation carriers [2, 18, 20]. Hence, MSI testing in patients with CMMRD, particularly those with MSH6 deficiency may not provide conclusive results. Instead of MSI testing, MMR-IHC could provide more information on the MMR status of patients with CMMRD [20]. These previous reports are consistent with our patient who had MSS and TMB-H, but had heterogeneous MMR-IHC status to which the molecular mechanism is difficult to explain. However, concurrent MSS and TMB-H have been observed in 3% of CRC patients, with approximately 7.3% patients with MSS/TMB-H CRC also harboring MSH6 mutations [21].
Due to the increase in mutations resulting from the impaired DNA repair mechanisms in CMMRD, ICIs have been explored as a potential strategy in treating cancers in patients with CMMRD [9–13]. In contrast with previously reported data [9–13], no significant clinical response was observed from the primary colonic lesions of our patient. His lack of initial response to ICI may be due to tumor heterogeneity, wherein only the dMMR part of his tumor responded to the ICI while the pMMR region remained immunosuppressed. Heterogeneous MLH1 expression was implicated as the mechanism of failed response to ICI in a patient with dMMR gastric cancer [22]. Interestingly, the addition of regorafenib potentially contributed to making the tumor more “immune reactive” as compared to the use of only ICIs. Despite the MSS status of our patient, his clinical benefit to anti-PD-1 monoclonal antibody pembrolizumab in combination with a multi-kinase inhibitor regorafenib was consistent with ICI response of MSS/TMB-H CRC described in a previous study [21]. Unfortunately, due to financial issues, expression levels of various markers of tumor microenvironment were not analyzed.
In conclusion, our case highlights the importance of the inclusion of targeted sequencing in addition to MMR/MSI testing of patients with CRC to understand the genetic landscape and identify potential hereditary factors. Moreover, the evaluation of multiple specimens is also necessary to generate conclusive results.
Supplementary Information
Additional file 1: Figure S1. Microsatellite assessment by polymerase chain reaction (MSI-PCR of the two tumor blocks used for MMR-IHC were consistently assessed as microsatellite stable (MSS) (A-B). MSI-PCR of six mononucleotide microsatellite markers including NR21, Bat26, Bat25, NR27, NR24, and Mono27, two pentanucleotide microsatellite markers PentaC and PentaD, and an internal control, AmeI. Microsatellite instability with MSI-PCR is assessed as low (MSI-L) if having 1 marker exhibiting changes in length, and assessed as high (MSI-H) when having 2 or more markers exhibiting increase or decrease in length of microsatellite markers. MSS is assessed when all markers have no change. Figure S2. Detection of germline homozygous MSH6 missense mutation in the patient. A. Illustration of the homozygous germline MSH6 c.3226C>T (p.R1076C) of the patient using the Integrated Genome Viewer. B. Pedigree analysis illustrating the family history of cancer and the detection of homozygous MSH6 R1076C mutation in the patient (III.1) and heterozygous MSH6 R1076C mutation in the parents of the patient (II.1 and II.2), his wife (III.2) and his two daughters (IV.1 an IV.2). (PPTX 335 kb)
Additional file 2: Table S1. Summary of targeted sequencing results from 2 tissue samples and blood sample of the patient. Table S2. Review of literature on CMMRD patients treated with immune checkpoint inhibitors.
Abbreviations
CMMRDConstitutional mismatch repair deficiency
CRCColorectal cancer
dMMRDeficiency in mismatch repair
FFPEFormalin-fixed paraffin-embedded
HNPCCHereditary non-polyposis colorectal cancer
ICIImmune checkpoint inhibitor
IHCImmunohistochemistry
MMRMismatch repair
MSIMicrosatellite instability
MSSMicrosatellite stable
NCCNNational Comprehensive Cancer Network
PCRPolymerase chain reaction
pMMRProficient in mismatch repair
TMBTumor mutation burden
TMB-HHigh TMB
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patient and his family. We also thank the investigators, study coordinators, operation staff and the whole project team who worked on this case.
Authors’ contributions
Tong Xie – contributed in the conception and design of the study and in the clinical data collection, analysis and interpretation; Qin Feng – contributed in the clinical data collection, analysis and interpretation; Zhongwu Li – contributed in the clinical data collection, analysis and interpretation; Ming Lu – contributed in the clinical data collection, analysis and interpretation; Jian Li – contributed in the clinical data collection, analysis and interpretation; Analyn Lizaso – contributed in the genomic data analysis and interpretation, drafting of manuscript; Jianxing Xiang – contributed in the genomic data analysis and interpretation, drafting of manuscript; Lu Zhang – contributed in the genomic data analysis and interpretation; Lin Shen– contributed in the conception and design of the study, involved in project supervision and administration; Zhi Peng – major contributor in conception and design of the study, involved in project supervision and administration, supervised manuscript writing. All the authors reviewed and approved the final version of the manuscript.
Funding
This work was supported by grants from the National Key Research and Development Program of China (Nos. 2017YFC1308900, 2017YFC0908400 to Z.P.), National Natural Science Foundation of China (No. 81602057 to Z.P.), Clinical Medicine Plus X - Young Scholars Project of Peking University (Nos. PKU2019LCXQ020, PKU2018LCXQ018 to Z.P.) and Beijing Municipal Administration of Hospital’s Youth Program (No. 20171102 to Z.P.). The funding agency had no role in the study design, data collection, analysis, interpretation, manuscript writing and decision to submit the article for publication.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the Declaration of Helsinki Declaration (as revised in 2013) and the ethical standards of the institutional and national research committees. The patient provided written informed consent for the publication of this report.
Competing interests
Analyn Lizaso, Jianxing Xiang, and Lu Zhang are employees of Burning Rock Biotech. The other authors declare no conflict of interest. | CETUXIMAB, FLUOROURACIL, OXALIPLATIN | DrugsGivenReaction | CC BY | 33422121 | 19,065,655 | 2021-01-09 |
What was the dosage of drug 'CETUXIMAB'? | Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review.
BACKGROUND
Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).
METHODS
We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.
CONCLUSIONS
Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
Background
The DNA mismatch repair (MMR) pathway functions to recognize and repair base pair mismatches that arise during DNA replication and recombination and plays a key role in maintaining genomic stability. Defects in mismatch repair (dMMR) account for approximately 15% of colorectal cancer (CRC) [1]. Approximately 3% of CRC are associated with Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer (HNPCC), an autosomal dominant disease and the most common inherited form of CRC arising from monoallelic germline mutation in MLH1, MSH2, MSH6, or PMS2 [2]. Another hereditary syndrome associated with dMMR is constitutional mismatch repair deficiency (CMMRD) syndrome, which is a rare autosomal recessive cancer-predisposing syndrome resulting from bi-allelic germline mutations in MMR genes [3].
National Comprehensive Cancer Network (NCCN) guideline now recommends all patients diagnosed with CRC to undergo MMR and microsatellite instability (MSI) testing to screen for inherited CRC, which is instrumental in identifying Lynch and CMMRD syndromes [4]. Proper diagnosis of these inherited cancer syndromes is necessary for optimal clinical management, including the decision to perform surgery and appropriate adjuvant chemotherapy [2, 5, 6]. However, tumor heterogeneity could contribute to inconsistent MMR-IHC or MSI results, which delays the diagnosis and affects the treatment outcomes [7, 8]. Herein, we report a patient with CMMRD and metastatic CRC resulting from bi-allelic germline MSH6 mutation who had heterogeneous MMR-IHC with high tumor mutations burden (TMB-H) but microsatellite stable (MSS) status that led to his complicated response to immune checkpoint inhibitor (ICI) therapy. We have prepared this manuscript in accordance with the CARE guidelines.
Case presentation
In November 2016, a 32-year-old male presented with a chief complaint of hematochezia for 2 years was diagnosed with early-onset colon cancer with peritoneal metastasis (T4bN1M1). Abdominal computed tomography (CT) scans showed a mass in the splenic flexure of the colon with presence of multiple peritoneal nodules (Fig. 1). Additionally, histopathology examination of the tissue biopsy revealed poorly- to moderately-differentiated adenocarcinoma with mucinous features. Palliative first-line FOLFOXIRI regimen (D1: 5-fluorouracil 2.8 g/m2 5g civ46 + oxaliplatin 85 mg/m2 150mg + irinotecan 165 mg/m2 300mg q14d) was administered for a total of 6 cycles achieving stable disease (SD) (Fig. 1). On March 2017, laparotomy and subtotal colectomy was performed with no postoperative complications and confirmed the pathological stage of pT4bN1a. Immunohistochemistry (MMR-IHC) of different sections of formalin-fixed paraffin-embedded (FFPE) blocks of the surgically-removed tumor demonstrated heterogeneity in MMR status, with one section demonstrating complete loss of MSH6 expression and evaluated as MMR deficient (dMMR) (Fig. 2a), while another section demonstrating clonal loss of MSH6 (Fig. 2b, MSH6-1X), but still evaluated as MMR proficient (pMMR) due to moderate staining in some clones (Fig. 2b). However, the MSI status of both blocks was determined as MSS by polymerase chain reaction (PCR)–based analysis (Fig. S1). To further understand the biology of this heterogeneity, two tissue specimens used for MMR-IHC and an additional plasma sample were submitted for comprehensive targeted sequencing with a 520-gene panel (OncoScreen Plus, Burning Rock Biotech). Table S1 summarizes the sequencing results. The tumor mutation burden (TMB) status of all his samples was assessed to be TMB-H. Careful inspection of the mutation profile revealed that the pMMR tissue sample and blood sample had similar mutation profile and different from the dMMR sample. Despite the variability in mutation profile between the pMMR and dMMR tissue samples, a homozygous missense mutation in the exon 5 of MSH6 gene, c.3226C > T (p.R1076C), was consistently detected in both tissue samples and blood sample. In addition to the consistent wild-type status for HRAS, KRAS, and NRAS, a SMAD4 R361H was also consistently detected in all his samples. Homozygous germline mutation status of MSH6 R1076C was also confirmed using lymphocyte-derived genomic DNA analysis (Fig. S2A). Further investigations of his family history revealed that his paternal grandfather and maternal grandmother had stomach cancer and endometrial cancer, respectively (Fig. S2B, I.1 and I.2). He was born from fourth-degree consanguineous parents. His back and abdomen are scattered with multiple café-au-lait macula and neurofibromas with unknown age of occurrence. His daughters were born with blue birthmark. Moreover, genetic testing of his immediate family members revealed heterozygous MSH6 R1076C, strongly indicating an autosomal recessive inheritance pattern (Fig. S2B). Based on his clinical and genetic data, he was additionally diagnosed with late-onset CMMRD.
Fig. 1 Summary of the treatment received by the patient, including the best objective response (OR) and progression-free survival (PFS) in each line of treatment. Abdominal computed tomography (CT) scans are also provided. Red arrows indicate the primary lesions
Fig. 2 Immunohistochemical staining of MSH6, MSH2, MLH1, and PMS2. One section of the surgical tissue sample was evaluated as (a) MMR deficient (dMMR) and the other as (b) MMR proficient (pMMR). Hematoxylin Eosin staining, MSH6, MSH2, MLH1 and PMS2 were collected at 4X magnification, unless otherwise indicated (i.e. magnification of 1X for MSH6 in the second panel on top)
Since post-colectomy, he was administered with FOLFOX and cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + cetuximab 500 mg/kg q14d) for 8 cycles achieving SD. He experienced leukopenia multiple times throughout the treatment process. In March 2018, disease recurrence was suspected after a review of abdominal CT revealed a ring-shaped 50x31mm mass in the peritoneal folds of the anterior pelvic cavity. After reviewing literatures from MEDLINE, we found promising evidence of clinical response to ICI treatment in patients with CMMRD as summarized in Table S2 [9–13]. He was enrolled in a clinical trial for anti-PD-L1 monoclonal antibody CS1001–101 administered at 1200 mg in four-cycle regimen (NCT03744403). The treatment was well tolerated. Despite an unresponsive disease, he chose to remain on the treatment for another 4 cycles until confirmation of disease progression as per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. After immunotherapy was terminated, he was administered with FOLFOXIRI + cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + irinotecan 120 mg/m2 + cetuximab 500 mg/kg q14d) from November 2018 to October 2019 until progression. After the failure of one cycle ipilimumab (D1: 50 mg) and pembrolizumab (D1: 200 mg), pembrolizumab plus regorafenib (D1: pembrolizumab 200 mg, D1-D21 regorafenib 80 mg q21d) was administered in the next cycle (November 2019) considering the CMMRD and MSS status of the tumor. After 1 week of combination therapy, regorafenib was suspended due to grade 3 rash. Surprisingly, his clinical symptoms of CRC including abdominal pain were markedly relieved, which led to a remarkable improvement in his ECOG PS from 3 to 0. Serum tumor marker CEA also decreased from 13.18 ng/ml to 4.04 ng/ml within 1 month of combination therapy. After the rash resolved, he resumed regorafenib at a reduced dose of 40 mg qd without any chief complaint. His disease remains stable for 6 months as of the last follow-up on May 25, 2020.
Discussion
Due to the rarity of CMMRD, early diagnosis is challenging particularly in patients with no family history of cancer and delayed onset of malignancies. In our case, CMMRD was incidentally diagnosed due to the detection of bi-allelic germline MSH6 R1076C mutation by targeted sequencing. Targeted sequencing allowed the detection of the homozygous mutation which then led to further discovery of the presence of dermatological manifestations (i.e. café-au-lait spots and neurofibromas), family history of cancer, mutation carrier status of immediate family members, and consanguinity of the parents that all together helped in forming a conclusive diagnosis. His family has been appropriately counseled regarding their increased risk of developing cancer. Interestingly, our patient with CMMRD had TMB-H but failed to respond to anti-PD-L1 monotherapy with CS1001–101 and combined therapy of anti-PD-1 and anti-CTLA-4 monoclonal antibodies, which may be due to tumor heterogeneity and MSS status. However, the addition of an anti-VEGFR2 multi-kinase inhibitor regorafenib to the anti-PD-1 therapy was clinically effective for our patient.
CMMRD is associated with poor prognosis and typically manifested as childhood cancers including brain tumors, hematological malignancies, and gastrointestinal tumors [3, 5]. Missense R1076C mutation of MSH6 gene is located on the ATPase domain and has been evaluated as likely pathogenic in ClinVar database (Variation ID: 89357) with multiple evidence associating this mutation with HNPCC and hereditary cancer-predisposing syndrome. Bi-allelic germline MSH6 R1076C mutation was also reported in a 45-year-old patient diagnosed with CRC [14]. The phenotype presentation in the patients with mono-allelic or bi-allelic MSH6 R1076C seemed to be milder compared with those with bi-allelic mutations in other MMR genes [14–16]. Delayed age of onset has generally been observed for MSH6 mutation carriers as compared to MSH2 or MLH1 mutants [17–19]. Moreover, MSH6 missense mutation carriers were more likely to develop CRC than those with truncating mutations [18]. Consistently, bi-allelic germline MSH6 R1076C mutation of our patient led to the development of CRC in the third decade of life but without any hematological malignancy or brain tumor. According to the report by Plaschke and colleagues, the hypomorphic nature of MSH6 missense mutation might only bring about partial abolishment of its protein function [15]. This hypomorphic mutation might also explain the intratumor genetic heterogeneity demonstrated by heterogeneous MMR-IHC status and distinct mutation profile of the two tumor block samples from our patient.
Conventionally, the complete absence of MSH6 nuclear staining in both tumor and normal cells of the colonic mucosa is typically observed in patients with bi-allelic MSH6 mutation [14–16]. However, MSI is not always present among MSH6 mutation carriers [2, 18, 20]. Hence, MSI testing in patients with CMMRD, particularly those with MSH6 deficiency may not provide conclusive results. Instead of MSI testing, MMR-IHC could provide more information on the MMR status of patients with CMMRD [20]. These previous reports are consistent with our patient who had MSS and TMB-H, but had heterogeneous MMR-IHC status to which the molecular mechanism is difficult to explain. However, concurrent MSS and TMB-H have been observed in 3% of CRC patients, with approximately 7.3% patients with MSS/TMB-H CRC also harboring MSH6 mutations [21].
Due to the increase in mutations resulting from the impaired DNA repair mechanisms in CMMRD, ICIs have been explored as a potential strategy in treating cancers in patients with CMMRD [9–13]. In contrast with previously reported data [9–13], no significant clinical response was observed from the primary colonic lesions of our patient. His lack of initial response to ICI may be due to tumor heterogeneity, wherein only the dMMR part of his tumor responded to the ICI while the pMMR region remained immunosuppressed. Heterogeneous MLH1 expression was implicated as the mechanism of failed response to ICI in a patient with dMMR gastric cancer [22]. Interestingly, the addition of regorafenib potentially contributed to making the tumor more “immune reactive” as compared to the use of only ICIs. Despite the MSS status of our patient, his clinical benefit to anti-PD-1 monoclonal antibody pembrolizumab in combination with a multi-kinase inhibitor regorafenib was consistent with ICI response of MSS/TMB-H CRC described in a previous study [21]. Unfortunately, due to financial issues, expression levels of various markers of tumor microenvironment were not analyzed.
In conclusion, our case highlights the importance of the inclusion of targeted sequencing in addition to MMR/MSI testing of patients with CRC to understand the genetic landscape and identify potential hereditary factors. Moreover, the evaluation of multiple specimens is also necessary to generate conclusive results.
Supplementary Information
Additional file 1: Figure S1. Microsatellite assessment by polymerase chain reaction (MSI-PCR of the two tumor blocks used for MMR-IHC were consistently assessed as microsatellite stable (MSS) (A-B). MSI-PCR of six mononucleotide microsatellite markers including NR21, Bat26, Bat25, NR27, NR24, and Mono27, two pentanucleotide microsatellite markers PentaC and PentaD, and an internal control, AmeI. Microsatellite instability with MSI-PCR is assessed as low (MSI-L) if having 1 marker exhibiting changes in length, and assessed as high (MSI-H) when having 2 or more markers exhibiting increase or decrease in length of microsatellite markers. MSS is assessed when all markers have no change. Figure S2. Detection of germline homozygous MSH6 missense mutation in the patient. A. Illustration of the homozygous germline MSH6 c.3226C>T (p.R1076C) of the patient using the Integrated Genome Viewer. B. Pedigree analysis illustrating the family history of cancer and the detection of homozygous MSH6 R1076C mutation in the patient (III.1) and heterozygous MSH6 R1076C mutation in the parents of the patient (II.1 and II.2), his wife (III.2) and his two daughters (IV.1 an IV.2). (PPTX 335 kb)
Additional file 2: Table S1. Summary of targeted sequencing results from 2 tissue samples and blood sample of the patient. Table S2. Review of literature on CMMRD patients treated with immune checkpoint inhibitors.
Abbreviations
CMMRDConstitutional mismatch repair deficiency
CRCColorectal cancer
dMMRDeficiency in mismatch repair
FFPEFormalin-fixed paraffin-embedded
HNPCCHereditary non-polyposis colorectal cancer
ICIImmune checkpoint inhibitor
IHCImmunohistochemistry
MMRMismatch repair
MSIMicrosatellite instability
MSSMicrosatellite stable
NCCNNational Comprehensive Cancer Network
PCRPolymerase chain reaction
pMMRProficient in mismatch repair
TMBTumor mutation burden
TMB-HHigh TMB
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patient and his family. We also thank the investigators, study coordinators, operation staff and the whole project team who worked on this case.
Authors’ contributions
Tong Xie – contributed in the conception and design of the study and in the clinical data collection, analysis and interpretation; Qin Feng – contributed in the clinical data collection, analysis and interpretation; Zhongwu Li – contributed in the clinical data collection, analysis and interpretation; Ming Lu – contributed in the clinical data collection, analysis and interpretation; Jian Li – contributed in the clinical data collection, analysis and interpretation; Analyn Lizaso – contributed in the genomic data analysis and interpretation, drafting of manuscript; Jianxing Xiang – contributed in the genomic data analysis and interpretation, drafting of manuscript; Lu Zhang – contributed in the genomic data analysis and interpretation; Lin Shen– contributed in the conception and design of the study, involved in project supervision and administration; Zhi Peng – major contributor in conception and design of the study, involved in project supervision and administration, supervised manuscript writing. All the authors reviewed and approved the final version of the manuscript.
Funding
This work was supported by grants from the National Key Research and Development Program of China (Nos. 2017YFC1308900, 2017YFC0908400 to Z.P.), National Natural Science Foundation of China (No. 81602057 to Z.P.), Clinical Medicine Plus X - Young Scholars Project of Peking University (Nos. PKU2019LCXQ020, PKU2018LCXQ018 to Z.P.) and Beijing Municipal Administration of Hospital’s Youth Program (No. 20171102 to Z.P.). The funding agency had no role in the study design, data collection, analysis, interpretation, manuscript writing and decision to submit the article for publication.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the Declaration of Helsinki Declaration (as revised in 2013) and the ethical standards of the institutional and national research committees. The patient provided written informed consent for the publication of this report.
Competing interests
Analyn Lizaso, Jianxing Xiang, and Lu Zhang are employees of Burning Rock Biotech. The other authors declare no conflict of interest. | 500 MG/KG Q14D; FOR 8 CYCLES | DrugDosageText | CC BY | 33422121 | 19,065,655 | 2021-01-09 |
What was the dosage of drug 'FLUOROURACIL'? | Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review.
BACKGROUND
Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).
METHODS
We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.
CONCLUSIONS
Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
Background
The DNA mismatch repair (MMR) pathway functions to recognize and repair base pair mismatches that arise during DNA replication and recombination and plays a key role in maintaining genomic stability. Defects in mismatch repair (dMMR) account for approximately 15% of colorectal cancer (CRC) [1]. Approximately 3% of CRC are associated with Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer (HNPCC), an autosomal dominant disease and the most common inherited form of CRC arising from monoallelic germline mutation in MLH1, MSH2, MSH6, or PMS2 [2]. Another hereditary syndrome associated with dMMR is constitutional mismatch repair deficiency (CMMRD) syndrome, which is a rare autosomal recessive cancer-predisposing syndrome resulting from bi-allelic germline mutations in MMR genes [3].
National Comprehensive Cancer Network (NCCN) guideline now recommends all patients diagnosed with CRC to undergo MMR and microsatellite instability (MSI) testing to screen for inherited CRC, which is instrumental in identifying Lynch and CMMRD syndromes [4]. Proper diagnosis of these inherited cancer syndromes is necessary for optimal clinical management, including the decision to perform surgery and appropriate adjuvant chemotherapy [2, 5, 6]. However, tumor heterogeneity could contribute to inconsistent MMR-IHC or MSI results, which delays the diagnosis and affects the treatment outcomes [7, 8]. Herein, we report a patient with CMMRD and metastatic CRC resulting from bi-allelic germline MSH6 mutation who had heterogeneous MMR-IHC with high tumor mutations burden (TMB-H) but microsatellite stable (MSS) status that led to his complicated response to immune checkpoint inhibitor (ICI) therapy. We have prepared this manuscript in accordance with the CARE guidelines.
Case presentation
In November 2016, a 32-year-old male presented with a chief complaint of hematochezia for 2 years was diagnosed with early-onset colon cancer with peritoneal metastasis (T4bN1M1). Abdominal computed tomography (CT) scans showed a mass in the splenic flexure of the colon with presence of multiple peritoneal nodules (Fig. 1). Additionally, histopathology examination of the tissue biopsy revealed poorly- to moderately-differentiated adenocarcinoma with mucinous features. Palliative first-line FOLFOXIRI regimen (D1: 5-fluorouracil 2.8 g/m2 5g civ46 + oxaliplatin 85 mg/m2 150mg + irinotecan 165 mg/m2 300mg q14d) was administered for a total of 6 cycles achieving stable disease (SD) (Fig. 1). On March 2017, laparotomy and subtotal colectomy was performed with no postoperative complications and confirmed the pathological stage of pT4bN1a. Immunohistochemistry (MMR-IHC) of different sections of formalin-fixed paraffin-embedded (FFPE) blocks of the surgically-removed tumor demonstrated heterogeneity in MMR status, with one section demonstrating complete loss of MSH6 expression and evaluated as MMR deficient (dMMR) (Fig. 2a), while another section demonstrating clonal loss of MSH6 (Fig. 2b, MSH6-1X), but still evaluated as MMR proficient (pMMR) due to moderate staining in some clones (Fig. 2b). However, the MSI status of both blocks was determined as MSS by polymerase chain reaction (PCR)–based analysis (Fig. S1). To further understand the biology of this heterogeneity, two tissue specimens used for MMR-IHC and an additional plasma sample were submitted for comprehensive targeted sequencing with a 520-gene panel (OncoScreen Plus, Burning Rock Biotech). Table S1 summarizes the sequencing results. The tumor mutation burden (TMB) status of all his samples was assessed to be TMB-H. Careful inspection of the mutation profile revealed that the pMMR tissue sample and blood sample had similar mutation profile and different from the dMMR sample. Despite the variability in mutation profile between the pMMR and dMMR tissue samples, a homozygous missense mutation in the exon 5 of MSH6 gene, c.3226C > T (p.R1076C), was consistently detected in both tissue samples and blood sample. In addition to the consistent wild-type status for HRAS, KRAS, and NRAS, a SMAD4 R361H was also consistently detected in all his samples. Homozygous germline mutation status of MSH6 R1076C was also confirmed using lymphocyte-derived genomic DNA analysis (Fig. S2A). Further investigations of his family history revealed that his paternal grandfather and maternal grandmother had stomach cancer and endometrial cancer, respectively (Fig. S2B, I.1 and I.2). He was born from fourth-degree consanguineous parents. His back and abdomen are scattered with multiple café-au-lait macula and neurofibromas with unknown age of occurrence. His daughters were born with blue birthmark. Moreover, genetic testing of his immediate family members revealed heterozygous MSH6 R1076C, strongly indicating an autosomal recessive inheritance pattern (Fig. S2B). Based on his clinical and genetic data, he was additionally diagnosed with late-onset CMMRD.
Fig. 1 Summary of the treatment received by the patient, including the best objective response (OR) and progression-free survival (PFS) in each line of treatment. Abdominal computed tomography (CT) scans are also provided. Red arrows indicate the primary lesions
Fig. 2 Immunohistochemical staining of MSH6, MSH2, MLH1, and PMS2. One section of the surgical tissue sample was evaluated as (a) MMR deficient (dMMR) and the other as (b) MMR proficient (pMMR). Hematoxylin Eosin staining, MSH6, MSH2, MLH1 and PMS2 were collected at 4X magnification, unless otherwise indicated (i.e. magnification of 1X for MSH6 in the second panel on top)
Since post-colectomy, he was administered with FOLFOX and cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + cetuximab 500 mg/kg q14d) for 8 cycles achieving SD. He experienced leukopenia multiple times throughout the treatment process. In March 2018, disease recurrence was suspected after a review of abdominal CT revealed a ring-shaped 50x31mm mass in the peritoneal folds of the anterior pelvic cavity. After reviewing literatures from MEDLINE, we found promising evidence of clinical response to ICI treatment in patients with CMMRD as summarized in Table S2 [9–13]. He was enrolled in a clinical trial for anti-PD-L1 monoclonal antibody CS1001–101 administered at 1200 mg in four-cycle regimen (NCT03744403). The treatment was well tolerated. Despite an unresponsive disease, he chose to remain on the treatment for another 4 cycles until confirmation of disease progression as per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. After immunotherapy was terminated, he was administered with FOLFOXIRI + cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + irinotecan 120 mg/m2 + cetuximab 500 mg/kg q14d) from November 2018 to October 2019 until progression. After the failure of one cycle ipilimumab (D1: 50 mg) and pembrolizumab (D1: 200 mg), pembrolizumab plus regorafenib (D1: pembrolizumab 200 mg, D1-D21 regorafenib 80 mg q21d) was administered in the next cycle (November 2019) considering the CMMRD and MSS status of the tumor. After 1 week of combination therapy, regorafenib was suspended due to grade 3 rash. Surprisingly, his clinical symptoms of CRC including abdominal pain were markedly relieved, which led to a remarkable improvement in his ECOG PS from 3 to 0. Serum tumor marker CEA also decreased from 13.18 ng/ml to 4.04 ng/ml within 1 month of combination therapy. After the rash resolved, he resumed regorafenib at a reduced dose of 40 mg qd without any chief complaint. His disease remains stable for 6 months as of the last follow-up on May 25, 2020.
Discussion
Due to the rarity of CMMRD, early diagnosis is challenging particularly in patients with no family history of cancer and delayed onset of malignancies. In our case, CMMRD was incidentally diagnosed due to the detection of bi-allelic germline MSH6 R1076C mutation by targeted sequencing. Targeted sequencing allowed the detection of the homozygous mutation which then led to further discovery of the presence of dermatological manifestations (i.e. café-au-lait spots and neurofibromas), family history of cancer, mutation carrier status of immediate family members, and consanguinity of the parents that all together helped in forming a conclusive diagnosis. His family has been appropriately counseled regarding their increased risk of developing cancer. Interestingly, our patient with CMMRD had TMB-H but failed to respond to anti-PD-L1 monotherapy with CS1001–101 and combined therapy of anti-PD-1 and anti-CTLA-4 monoclonal antibodies, which may be due to tumor heterogeneity and MSS status. However, the addition of an anti-VEGFR2 multi-kinase inhibitor regorafenib to the anti-PD-1 therapy was clinically effective for our patient.
CMMRD is associated with poor prognosis and typically manifested as childhood cancers including brain tumors, hematological malignancies, and gastrointestinal tumors [3, 5]. Missense R1076C mutation of MSH6 gene is located on the ATPase domain and has been evaluated as likely pathogenic in ClinVar database (Variation ID: 89357) with multiple evidence associating this mutation with HNPCC and hereditary cancer-predisposing syndrome. Bi-allelic germline MSH6 R1076C mutation was also reported in a 45-year-old patient diagnosed with CRC [14]. The phenotype presentation in the patients with mono-allelic or bi-allelic MSH6 R1076C seemed to be milder compared with those with bi-allelic mutations in other MMR genes [14–16]. Delayed age of onset has generally been observed for MSH6 mutation carriers as compared to MSH2 or MLH1 mutants [17–19]. Moreover, MSH6 missense mutation carriers were more likely to develop CRC than those with truncating mutations [18]. Consistently, bi-allelic germline MSH6 R1076C mutation of our patient led to the development of CRC in the third decade of life but without any hematological malignancy or brain tumor. According to the report by Plaschke and colleagues, the hypomorphic nature of MSH6 missense mutation might only bring about partial abolishment of its protein function [15]. This hypomorphic mutation might also explain the intratumor genetic heterogeneity demonstrated by heterogeneous MMR-IHC status and distinct mutation profile of the two tumor block samples from our patient.
Conventionally, the complete absence of MSH6 nuclear staining in both tumor and normal cells of the colonic mucosa is typically observed in patients with bi-allelic MSH6 mutation [14–16]. However, MSI is not always present among MSH6 mutation carriers [2, 18, 20]. Hence, MSI testing in patients with CMMRD, particularly those with MSH6 deficiency may not provide conclusive results. Instead of MSI testing, MMR-IHC could provide more information on the MMR status of patients with CMMRD [20]. These previous reports are consistent with our patient who had MSS and TMB-H, but had heterogeneous MMR-IHC status to which the molecular mechanism is difficult to explain. However, concurrent MSS and TMB-H have been observed in 3% of CRC patients, with approximately 7.3% patients with MSS/TMB-H CRC also harboring MSH6 mutations [21].
Due to the increase in mutations resulting from the impaired DNA repair mechanisms in CMMRD, ICIs have been explored as a potential strategy in treating cancers in patients with CMMRD [9–13]. In contrast with previously reported data [9–13], no significant clinical response was observed from the primary colonic lesions of our patient. His lack of initial response to ICI may be due to tumor heterogeneity, wherein only the dMMR part of his tumor responded to the ICI while the pMMR region remained immunosuppressed. Heterogeneous MLH1 expression was implicated as the mechanism of failed response to ICI in a patient with dMMR gastric cancer [22]. Interestingly, the addition of regorafenib potentially contributed to making the tumor more “immune reactive” as compared to the use of only ICIs. Despite the MSS status of our patient, his clinical benefit to anti-PD-1 monoclonal antibody pembrolizumab in combination with a multi-kinase inhibitor regorafenib was consistent with ICI response of MSS/TMB-H CRC described in a previous study [21]. Unfortunately, due to financial issues, expression levels of various markers of tumor microenvironment were not analyzed.
In conclusion, our case highlights the importance of the inclusion of targeted sequencing in addition to MMR/MSI testing of patients with CRC to understand the genetic landscape and identify potential hereditary factors. Moreover, the evaluation of multiple specimens is also necessary to generate conclusive results.
Supplementary Information
Additional file 1: Figure S1. Microsatellite assessment by polymerase chain reaction (MSI-PCR of the two tumor blocks used for MMR-IHC were consistently assessed as microsatellite stable (MSS) (A-B). MSI-PCR of six mononucleotide microsatellite markers including NR21, Bat26, Bat25, NR27, NR24, and Mono27, two pentanucleotide microsatellite markers PentaC and PentaD, and an internal control, AmeI. Microsatellite instability with MSI-PCR is assessed as low (MSI-L) if having 1 marker exhibiting changes in length, and assessed as high (MSI-H) when having 2 or more markers exhibiting increase or decrease in length of microsatellite markers. MSS is assessed when all markers have no change. Figure S2. Detection of germline homozygous MSH6 missense mutation in the patient. A. Illustration of the homozygous germline MSH6 c.3226C>T (p.R1076C) of the patient using the Integrated Genome Viewer. B. Pedigree analysis illustrating the family history of cancer and the detection of homozygous MSH6 R1076C mutation in the patient (III.1) and heterozygous MSH6 R1076C mutation in the parents of the patient (II.1 and II.2), his wife (III.2) and his two daughters (IV.1 an IV.2). (PPTX 335 kb)
Additional file 2: Table S1. Summary of targeted sequencing results from 2 tissue samples and blood sample of the patient. Table S2. Review of literature on CMMRD patients treated with immune checkpoint inhibitors.
Abbreviations
CMMRDConstitutional mismatch repair deficiency
CRCColorectal cancer
dMMRDeficiency in mismatch repair
FFPEFormalin-fixed paraffin-embedded
HNPCCHereditary non-polyposis colorectal cancer
ICIImmune checkpoint inhibitor
IHCImmunohistochemistry
MMRMismatch repair
MSIMicrosatellite instability
MSSMicrosatellite stable
NCCNNational Comprehensive Cancer Network
PCRPolymerase chain reaction
pMMRProficient in mismatch repair
TMBTumor mutation burden
TMB-HHigh TMB
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patient and his family. We also thank the investigators, study coordinators, operation staff and the whole project team who worked on this case.
Authors’ contributions
Tong Xie – contributed in the conception and design of the study and in the clinical data collection, analysis and interpretation; Qin Feng – contributed in the clinical data collection, analysis and interpretation; Zhongwu Li – contributed in the clinical data collection, analysis and interpretation; Ming Lu – contributed in the clinical data collection, analysis and interpretation; Jian Li – contributed in the clinical data collection, analysis and interpretation; Analyn Lizaso – contributed in the genomic data analysis and interpretation, drafting of manuscript; Jianxing Xiang – contributed in the genomic data analysis and interpretation, drafting of manuscript; Lu Zhang – contributed in the genomic data analysis and interpretation; Lin Shen– contributed in the conception and design of the study, involved in project supervision and administration; Zhi Peng – major contributor in conception and design of the study, involved in project supervision and administration, supervised manuscript writing. All the authors reviewed and approved the final version of the manuscript.
Funding
This work was supported by grants from the National Key Research and Development Program of China (Nos. 2017YFC1308900, 2017YFC0908400 to Z.P.), National Natural Science Foundation of China (No. 81602057 to Z.P.), Clinical Medicine Plus X - Young Scholars Project of Peking University (Nos. PKU2019LCXQ020, PKU2018LCXQ018 to Z.P.) and Beijing Municipal Administration of Hospital’s Youth Program (No. 20171102 to Z.P.). The funding agency had no role in the study design, data collection, analysis, interpretation, manuscript writing and decision to submit the article for publication.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the Declaration of Helsinki Declaration (as revised in 2013) and the ethical standards of the institutional and national research committees. The patient provided written informed consent for the publication of this report.
Competing interests
Analyn Lizaso, Jianxing Xiang, and Lu Zhang are employees of Burning Rock Biotech. The other authors declare no conflict of interest. | FOR 8 CYCLES | DrugDosageText | CC BY | 33422121 | 19,065,655 | 2021-01-09 |
What was the dosage of drug 'OXALIPLATIN'? | Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review.
BACKGROUND
Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).
METHODS
We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.
CONCLUSIONS
Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
Background
The DNA mismatch repair (MMR) pathway functions to recognize and repair base pair mismatches that arise during DNA replication and recombination and plays a key role in maintaining genomic stability. Defects in mismatch repair (dMMR) account for approximately 15% of colorectal cancer (CRC) [1]. Approximately 3% of CRC are associated with Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer (HNPCC), an autosomal dominant disease and the most common inherited form of CRC arising from monoallelic germline mutation in MLH1, MSH2, MSH6, or PMS2 [2]. Another hereditary syndrome associated with dMMR is constitutional mismatch repair deficiency (CMMRD) syndrome, which is a rare autosomal recessive cancer-predisposing syndrome resulting from bi-allelic germline mutations in MMR genes [3].
National Comprehensive Cancer Network (NCCN) guideline now recommends all patients diagnosed with CRC to undergo MMR and microsatellite instability (MSI) testing to screen for inherited CRC, which is instrumental in identifying Lynch and CMMRD syndromes [4]. Proper diagnosis of these inherited cancer syndromes is necessary for optimal clinical management, including the decision to perform surgery and appropriate adjuvant chemotherapy [2, 5, 6]. However, tumor heterogeneity could contribute to inconsistent MMR-IHC or MSI results, which delays the diagnosis and affects the treatment outcomes [7, 8]. Herein, we report a patient with CMMRD and metastatic CRC resulting from bi-allelic germline MSH6 mutation who had heterogeneous MMR-IHC with high tumor mutations burden (TMB-H) but microsatellite stable (MSS) status that led to his complicated response to immune checkpoint inhibitor (ICI) therapy. We have prepared this manuscript in accordance with the CARE guidelines.
Case presentation
In November 2016, a 32-year-old male presented with a chief complaint of hematochezia for 2 years was diagnosed with early-onset colon cancer with peritoneal metastasis (T4bN1M1). Abdominal computed tomography (CT) scans showed a mass in the splenic flexure of the colon with presence of multiple peritoneal nodules (Fig. 1). Additionally, histopathology examination of the tissue biopsy revealed poorly- to moderately-differentiated adenocarcinoma with mucinous features. Palliative first-line FOLFOXIRI regimen (D1: 5-fluorouracil 2.8 g/m2 5g civ46 + oxaliplatin 85 mg/m2 150mg + irinotecan 165 mg/m2 300mg q14d) was administered for a total of 6 cycles achieving stable disease (SD) (Fig. 1). On March 2017, laparotomy and subtotal colectomy was performed with no postoperative complications and confirmed the pathological stage of pT4bN1a. Immunohistochemistry (MMR-IHC) of different sections of formalin-fixed paraffin-embedded (FFPE) blocks of the surgically-removed tumor demonstrated heterogeneity in MMR status, with one section demonstrating complete loss of MSH6 expression and evaluated as MMR deficient (dMMR) (Fig. 2a), while another section demonstrating clonal loss of MSH6 (Fig. 2b, MSH6-1X), but still evaluated as MMR proficient (pMMR) due to moderate staining in some clones (Fig. 2b). However, the MSI status of both blocks was determined as MSS by polymerase chain reaction (PCR)–based analysis (Fig. S1). To further understand the biology of this heterogeneity, two tissue specimens used for MMR-IHC and an additional plasma sample were submitted for comprehensive targeted sequencing with a 520-gene panel (OncoScreen Plus, Burning Rock Biotech). Table S1 summarizes the sequencing results. The tumor mutation burden (TMB) status of all his samples was assessed to be TMB-H. Careful inspection of the mutation profile revealed that the pMMR tissue sample and blood sample had similar mutation profile and different from the dMMR sample. Despite the variability in mutation profile between the pMMR and dMMR tissue samples, a homozygous missense mutation in the exon 5 of MSH6 gene, c.3226C > T (p.R1076C), was consistently detected in both tissue samples and blood sample. In addition to the consistent wild-type status for HRAS, KRAS, and NRAS, a SMAD4 R361H was also consistently detected in all his samples. Homozygous germline mutation status of MSH6 R1076C was also confirmed using lymphocyte-derived genomic DNA analysis (Fig. S2A). Further investigations of his family history revealed that his paternal grandfather and maternal grandmother had stomach cancer and endometrial cancer, respectively (Fig. S2B, I.1 and I.2). He was born from fourth-degree consanguineous parents. His back and abdomen are scattered with multiple café-au-lait macula and neurofibromas with unknown age of occurrence. His daughters were born with blue birthmark. Moreover, genetic testing of his immediate family members revealed heterozygous MSH6 R1076C, strongly indicating an autosomal recessive inheritance pattern (Fig. S2B). Based on his clinical and genetic data, he was additionally diagnosed with late-onset CMMRD.
Fig. 1 Summary of the treatment received by the patient, including the best objective response (OR) and progression-free survival (PFS) in each line of treatment. Abdominal computed tomography (CT) scans are also provided. Red arrows indicate the primary lesions
Fig. 2 Immunohistochemical staining of MSH6, MSH2, MLH1, and PMS2. One section of the surgical tissue sample was evaluated as (a) MMR deficient (dMMR) and the other as (b) MMR proficient (pMMR). Hematoxylin Eosin staining, MSH6, MSH2, MLH1 and PMS2 were collected at 4X magnification, unless otherwise indicated (i.e. magnification of 1X for MSH6 in the second panel on top)
Since post-colectomy, he was administered with FOLFOX and cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + cetuximab 500 mg/kg q14d) for 8 cycles achieving SD. He experienced leukopenia multiple times throughout the treatment process. In March 2018, disease recurrence was suspected after a review of abdominal CT revealed a ring-shaped 50x31mm mass in the peritoneal folds of the anterior pelvic cavity. After reviewing literatures from MEDLINE, we found promising evidence of clinical response to ICI treatment in patients with CMMRD as summarized in Table S2 [9–13]. He was enrolled in a clinical trial for anti-PD-L1 monoclonal antibody CS1001–101 administered at 1200 mg in four-cycle regimen (NCT03744403). The treatment was well tolerated. Despite an unresponsive disease, he chose to remain on the treatment for another 4 cycles until confirmation of disease progression as per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. After immunotherapy was terminated, he was administered with FOLFOXIRI + cetuximab combination therapy (D1: 5-fluorouracil 2400 mg/m2 + oxaliplatin 85 mg/m2 + irinotecan 120 mg/m2 + cetuximab 500 mg/kg q14d) from November 2018 to October 2019 until progression. After the failure of one cycle ipilimumab (D1: 50 mg) and pembrolizumab (D1: 200 mg), pembrolizumab plus regorafenib (D1: pembrolizumab 200 mg, D1-D21 regorafenib 80 mg q21d) was administered in the next cycle (November 2019) considering the CMMRD and MSS status of the tumor. After 1 week of combination therapy, regorafenib was suspended due to grade 3 rash. Surprisingly, his clinical symptoms of CRC including abdominal pain were markedly relieved, which led to a remarkable improvement in his ECOG PS from 3 to 0. Serum tumor marker CEA also decreased from 13.18 ng/ml to 4.04 ng/ml within 1 month of combination therapy. After the rash resolved, he resumed regorafenib at a reduced dose of 40 mg qd without any chief complaint. His disease remains stable for 6 months as of the last follow-up on May 25, 2020.
Discussion
Due to the rarity of CMMRD, early diagnosis is challenging particularly in patients with no family history of cancer and delayed onset of malignancies. In our case, CMMRD was incidentally diagnosed due to the detection of bi-allelic germline MSH6 R1076C mutation by targeted sequencing. Targeted sequencing allowed the detection of the homozygous mutation which then led to further discovery of the presence of dermatological manifestations (i.e. café-au-lait spots and neurofibromas), family history of cancer, mutation carrier status of immediate family members, and consanguinity of the parents that all together helped in forming a conclusive diagnosis. His family has been appropriately counseled regarding their increased risk of developing cancer. Interestingly, our patient with CMMRD had TMB-H but failed to respond to anti-PD-L1 monotherapy with CS1001–101 and combined therapy of anti-PD-1 and anti-CTLA-4 monoclonal antibodies, which may be due to tumor heterogeneity and MSS status. However, the addition of an anti-VEGFR2 multi-kinase inhibitor regorafenib to the anti-PD-1 therapy was clinically effective for our patient.
CMMRD is associated with poor prognosis and typically manifested as childhood cancers including brain tumors, hematological malignancies, and gastrointestinal tumors [3, 5]. Missense R1076C mutation of MSH6 gene is located on the ATPase domain and has been evaluated as likely pathogenic in ClinVar database (Variation ID: 89357) with multiple evidence associating this mutation with HNPCC and hereditary cancer-predisposing syndrome. Bi-allelic germline MSH6 R1076C mutation was also reported in a 45-year-old patient diagnosed with CRC [14]. The phenotype presentation in the patients with mono-allelic or bi-allelic MSH6 R1076C seemed to be milder compared with those with bi-allelic mutations in other MMR genes [14–16]. Delayed age of onset has generally been observed for MSH6 mutation carriers as compared to MSH2 or MLH1 mutants [17–19]. Moreover, MSH6 missense mutation carriers were more likely to develop CRC than those with truncating mutations [18]. Consistently, bi-allelic germline MSH6 R1076C mutation of our patient led to the development of CRC in the third decade of life but without any hematological malignancy or brain tumor. According to the report by Plaschke and colleagues, the hypomorphic nature of MSH6 missense mutation might only bring about partial abolishment of its protein function [15]. This hypomorphic mutation might also explain the intratumor genetic heterogeneity demonstrated by heterogeneous MMR-IHC status and distinct mutation profile of the two tumor block samples from our patient.
Conventionally, the complete absence of MSH6 nuclear staining in both tumor and normal cells of the colonic mucosa is typically observed in patients with bi-allelic MSH6 mutation [14–16]. However, MSI is not always present among MSH6 mutation carriers [2, 18, 20]. Hence, MSI testing in patients with CMMRD, particularly those with MSH6 deficiency may not provide conclusive results. Instead of MSI testing, MMR-IHC could provide more information on the MMR status of patients with CMMRD [20]. These previous reports are consistent with our patient who had MSS and TMB-H, but had heterogeneous MMR-IHC status to which the molecular mechanism is difficult to explain. However, concurrent MSS and TMB-H have been observed in 3% of CRC patients, with approximately 7.3% patients with MSS/TMB-H CRC also harboring MSH6 mutations [21].
Due to the increase in mutations resulting from the impaired DNA repair mechanisms in CMMRD, ICIs have been explored as a potential strategy in treating cancers in patients with CMMRD [9–13]. In contrast with previously reported data [9–13], no significant clinical response was observed from the primary colonic lesions of our patient. His lack of initial response to ICI may be due to tumor heterogeneity, wherein only the dMMR part of his tumor responded to the ICI while the pMMR region remained immunosuppressed. Heterogeneous MLH1 expression was implicated as the mechanism of failed response to ICI in a patient with dMMR gastric cancer [22]. Interestingly, the addition of regorafenib potentially contributed to making the tumor more “immune reactive” as compared to the use of only ICIs. Despite the MSS status of our patient, his clinical benefit to anti-PD-1 monoclonal antibody pembrolizumab in combination with a multi-kinase inhibitor regorafenib was consistent with ICI response of MSS/TMB-H CRC described in a previous study [21]. Unfortunately, due to financial issues, expression levels of various markers of tumor microenvironment were not analyzed.
In conclusion, our case highlights the importance of the inclusion of targeted sequencing in addition to MMR/MSI testing of patients with CRC to understand the genetic landscape and identify potential hereditary factors. Moreover, the evaluation of multiple specimens is also necessary to generate conclusive results.
Supplementary Information
Additional file 1: Figure S1. Microsatellite assessment by polymerase chain reaction (MSI-PCR of the two tumor blocks used for MMR-IHC were consistently assessed as microsatellite stable (MSS) (A-B). MSI-PCR of six mononucleotide microsatellite markers including NR21, Bat26, Bat25, NR27, NR24, and Mono27, two pentanucleotide microsatellite markers PentaC and PentaD, and an internal control, AmeI. Microsatellite instability with MSI-PCR is assessed as low (MSI-L) if having 1 marker exhibiting changes in length, and assessed as high (MSI-H) when having 2 or more markers exhibiting increase or decrease in length of microsatellite markers. MSS is assessed when all markers have no change. Figure S2. Detection of germline homozygous MSH6 missense mutation in the patient. A. Illustration of the homozygous germline MSH6 c.3226C>T (p.R1076C) of the patient using the Integrated Genome Viewer. B. Pedigree analysis illustrating the family history of cancer and the detection of homozygous MSH6 R1076C mutation in the patient (III.1) and heterozygous MSH6 R1076C mutation in the parents of the patient (II.1 and II.2), his wife (III.2) and his two daughters (IV.1 an IV.2). (PPTX 335 kb)
Additional file 2: Table S1. Summary of targeted sequencing results from 2 tissue samples and blood sample of the patient. Table S2. Review of literature on CMMRD patients treated with immune checkpoint inhibitors.
Abbreviations
CMMRDConstitutional mismatch repair deficiency
CRCColorectal cancer
dMMRDeficiency in mismatch repair
FFPEFormalin-fixed paraffin-embedded
HNPCCHereditary non-polyposis colorectal cancer
ICIImmune checkpoint inhibitor
IHCImmunohistochemistry
MMRMismatch repair
MSIMicrosatellite instability
MSSMicrosatellite stable
NCCNNational Comprehensive Cancer Network
PCRPolymerase chain reaction
pMMRProficient in mismatch repair
TMBTumor mutation burden
TMB-HHigh TMB
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patient and his family. We also thank the investigators, study coordinators, operation staff and the whole project team who worked on this case.
Authors’ contributions
Tong Xie – contributed in the conception and design of the study and in the clinical data collection, analysis and interpretation; Qin Feng – contributed in the clinical data collection, analysis and interpretation; Zhongwu Li – contributed in the clinical data collection, analysis and interpretation; Ming Lu – contributed in the clinical data collection, analysis and interpretation; Jian Li – contributed in the clinical data collection, analysis and interpretation; Analyn Lizaso – contributed in the genomic data analysis and interpretation, drafting of manuscript; Jianxing Xiang – contributed in the genomic data analysis and interpretation, drafting of manuscript; Lu Zhang – contributed in the genomic data analysis and interpretation; Lin Shen– contributed in the conception and design of the study, involved in project supervision and administration; Zhi Peng – major contributor in conception and design of the study, involved in project supervision and administration, supervised manuscript writing. All the authors reviewed and approved the final version of the manuscript.
Funding
This work was supported by grants from the National Key Research and Development Program of China (Nos. 2017YFC1308900, 2017YFC0908400 to Z.P.), National Natural Science Foundation of China (No. 81602057 to Z.P.), Clinical Medicine Plus X - Young Scholars Project of Peking University (Nos. PKU2019LCXQ020, PKU2018LCXQ018 to Z.P.) and Beijing Municipal Administration of Hospital’s Youth Program (No. 20171102 to Z.P.). The funding agency had no role in the study design, data collection, analysis, interpretation, manuscript writing and decision to submit the article for publication.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the Declaration of Helsinki Declaration (as revised in 2013) and the ethical standards of the institutional and national research committees. The patient provided written informed consent for the publication of this report.
Competing interests
Analyn Lizaso, Jianxing Xiang, and Lu Zhang are employees of Burning Rock Biotech. The other authors declare no conflict of interest. | FOR 8 CYCLES | DrugDosageText | CC BY | 33422121 | 19,065,655 | 2021-01-09 |
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