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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | A case report of greater saphenous vein thrombosis in a patient with coronavirus (COVID-19) infection.
In December 2019, the World Health Organization (WHO) announced a series of pneumonia cases caused by an unknown origin, discovered in Wuhan, China. A dangerous virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a disease named acute respiratory syndrome, which was later popularly called coronavirus infection (COVID-19). Patients with acute COVID-19 are at high risk of thrombosis in various blood vessels due to hypercoagulability, blood stasis, and endothelial damage. In this study, we present a case report of a patient with COVID-19, who was hospitalized in one of the hospitals in Sanandaj, Iran. There were symptoms of fever, chills, muscle aches, cough, and tachycardia. Laboratory tests showed high levels of CRP, ESR, Ferritin CLIA, LDH and D-Dimer in this patient. Doppler ultrasound of the patient also revealed an abnormal finding, thrombosis in the right greater saphenous vein. This suggests that COVID-19 may lead to other negative effects through damage to blood vessels.
Introduction
Coronavirus has been widespread around the world since early 2020. The disease is highly contagious and, in severe cases, can lead to acute respiratory syndrome or organ failure [1, 2]. In January 2020, the World Health Organization (WHO) announced the outbreak of the disease as a “public health emergency of international concern” [3]. To date, the virus has led to an unprecedented global health crisis that has resulted in over 2 million death worldwide [4].
Several studies have shown that superficial vein thrombosis (SVT) is a common venous disease that appears to be medically benign but can cause serious complications and may be associated with complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE) [5, 6]. The prevalence of SVT is estimated to be about 3 to 11%, while the incidence of thrombosis in the greater saphenous vein (GSV) is about 60 to 80% of the time [7, 8]. The proximity of the greater saphenous vein to the saphenofemoral junction (SFJ) increases the possibility of displacement of blood clots and their entry into the deep venous system and as a result makes SVT a serious concern [9].
There is a risk for venous and arterial thrombosis in patients with SARS-Cov2 due to excessive coagulation status, blood stasis, and damage to vascular endothelial cells in this condition [10]. As the clinical signs of venous and arterial thrombosis are ambiguous, it is very important to use imaging techniques such as Doppler ultrasound and computed tomography (CT) angiography to prevent catastrophic complications such as pulmonary embolism and mortality [11]. In this case report, the course of a patient with coronavirus is described.
Case presentation
A 40-year-old man with one-week symptoms of cough, fever, fatigue, muscle aches, diarrhea, palpitations, and shortness of breath but no chest pain was admitted to Tohid Hospital, Sanandaj, Iran. Before admission, the patient was diagnosed with COVID-19 by an infectious disease specialist based on the initial symptoms. Both CT scans (Fig. 1) and the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed the infection. The patient had no history of underlying diseases such as diabetes, heart disease, hypertension, or cancer. At the hospital’s emergency department, the physical examinations showed that the patient had an irregular heart rate of 145 beats/min, blood pressure of 82/75 mmHg, temperature of 38.4 °C, respiratory rate of 26 breaths/min, and oxygen saturation of 89%. Paraclinical and laboratory results showed that routine blood tests, renal function, and electrolytes were completely normal. The influenza A and B antigen tests were also negative. However, the other laboratory findings were all abnormal, which are briefly listed in Table 1. In CT scans of the lungs (Fig. 1), bronchovascular marking is evident. Additionally, multiple foci of parenchymal turbidity and ground-glass opacity were observed with greater density at the margins and at the base of the lungs. Therefore, the patient was started on medical treatment with Naproxen, Hydroxychloroquine, Famotidine, Zinc, Neurobion, and anticoagulants by injecting heparin and taking acetylsalicylic acid tablets. Fig. 1 Axial without contrast-enhanced chest computed tomography (CT) image showing a coronavirus disease (COVID-19) infection
Table 1 The results of laboratory findings
Test Name Unit Reference range Results Flag
1 BUN mg/dl 6–20 32 Hi
2 CPK IU/L male: 0–171 55
3 LDH U/L 235–470 510 Hi
4 Na(ser) mEq/L 138–145 134 LOW
5 K(ser) mEq/L 3.6–5.9 3.8
6 Cr mg/dl male:0.8–1.3 mg/dl 0.7 LOW
7 CRP mg/l 0–6 30 Hi
8 ESR mm 5–12 18 Hi
9 Ferritin CLIA ng/mL 50–434 511 Hi
10 D-Dimer(CLIA-Siemens) ng/mL < 885 > 7500 Hi
Three days after hospitalization, Doppler ultrasound was performed on the lower limb due to numbness and tingling (paresthesia) in the right leg, in addition to swelling, redness, pain, and sensitivity to touch. Examination of the main veins of both lower limbs showed no evidence of occlusion in the external iliac, common femoral, popliteal, anterior and posterior tibialis, and peroneal. However, more detailed examination revealed that thrombosis was evident at the beginning of the greater saphenous vein of the right leg from distal to proximal (Fig. 2). The patient was discharged after 12 days of hospitalization with complete recovery from COVID-19. The anticoagulation treatment for the GSV thrombosis was continued for the patient, and no negative side effect caused by SVT was reported after the treatment. Fig. 2 Doppler ultrasound images of the lower right limb showing a superficial vein thrombosis (SVT). Anterior accessory saphenous vein (AASV), great saphenous vein (GSV), common femoral vein (CFV), and common femoral artery (CFA) in the Doppler ultrasound images of the lower right limb
Discussion
In this case report, we presented a patient with COVID-19 who was hospitalized in Tohid Hospital, Sanandaj, Iran and later was diagnosed with a thrombosis in his right GSV. This patient had common COVID-19 symptoms such as fever, dry cough, shortness of breath, and muscle pain [12] but no risk factor for SVT. Paraclinical tests and CT scans of the chest confirmed the COVID-19 diagnosis, and although there was no obvious evidence of SVT, detailed examination by Doppler ultrasound revealed a thrombosis in the patient’s GSV.
Studies have shown that the most important and stable hemostatic disorders associated with COVID-19 include mild thrombocytopenia [13] and an increase in D-dimer amount [14]. There is evidence showing thrombotic abnormalities, in addition to abnormalities in the function of various organs in patients with COVID-19 [15], which lead to higher mortality. However, as far as we can ascertain there are few reports of SVT and its side effects in patients with COVID-19.
Pathophysiologically, patients with COVID-19 may have a higher risk for developing venous thrombosis, usually due to diarrhea, hypotension, recurrent long-term infections, and dehydration [16]. Therefore, in patients with coronavirus, assessing the risk of DVT and SVT are essential to reduce complications and mortality risk. Studies have shown that patients prone to DVT usually have one of the following criteria: age over 75, respiratory and heart failure, history of previous thrombosis, acute onset of chronic pulmonary obstruction, acute cerebral infarction, malignant tumor, limb varicose veins, obesity, chronic kidney disease, inflammatory bowel disease, and more than 3 days of bed rest [17].
In one study on a patient with COVID-19, CT images of angiography showed signs of acute cerebral infarction and DVT in both lower limbs [18]. In our case report, the patient was suspected of having thromboembolism due to having similar lesions on his leg, however after a CT scan of his chest, his diagnosis with COVID-19 was confirmed, while there was no evidence of pulmonary thromboembolism. The physicians at the hospital also suspected SVT and DVT due to numbness, swelling, and pain in the right leg, which were examined by Doppler ultrasound of all blood vessels, including the common iliac, small saphenous, and greater saphenous. Since many studies have reported respiratory distress along with other clinical evidence of venous thrombosis, pulmonary embolism should be suspected [19, 20].
A recent study on the intensive care unit (ICU) patients with COVID-19 found that the rate of thrombotic disorders in these patients is 31% [21]. Further, medical images have shown that 27% of such thrombotic disorders are due to venous thromboembolism, 3.7% to arterial thrombosis, and 81% to pulmonary embolism, which is the most common complication of thrombosis in ICU patients [21]. The possible reasons for venous thrombosis may include the fact that COVID-19 attacks the human body via the 2-angiotensin converting enzyme, which is found in various blood vessels and organs of the body [22]. Ultimately, coronaviruses cause cytokine waterfalls, including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα in the body, which can increase the risk of complications such as blood clots. This cytokine storm can be associated with the severity of the disease and its negative consequences [23, 24]. Blood clots formed in DVT may also have a variety of causes, including vascular damage, surgery, special medications, and limited mobility [25], but the exact cause of COVID-19-induced DVT is still unknown [26].
Conclusion
COVID-19 is an emerging source of venous thrombosis due to factors such as excessive coagulation, blood stasis, and endothelial damage. The main mechanism of SVT and DVT formation due to COVID-19 is unknown and has not yet been examined. Although COVID-19 cases presented with SVT and DVT are rare, recognizing SVT and DVT as potential complications of COVID 19 infection will be of great value. Imaging techniques such as CT, MRI, and ultrasound can confirm the diagnosis of SVT and DVT. Due to the possibility of COVID-19 infection in patients presenting with venous thrombosis or other thromboembolic diseases, it seems important to consider the presence of COVID-19 in their diagnosis.
Acknowledgements
The authors thank all the teaching and medical staff of Kurdistan University of Medical Sciences for their effort in eradicating the virus around the clock.
Authors’ contributions
MBHS supervised the study and wrote the manuscript; PF collected the clinical data; MA and FF analyzed the data and images; and NHS reviewed the manuscript. The author(s) read and approved the final manuscript.
Funding
No source of funding.
Availability of data and materials
I have presented the data of the patient in the manuscript as a Table. I have submitted the figures separately as figures.
Declarations
Ethical approval and consent to participate
This research has been confirmed by the Research Center of Kurdistan University of Medical Sciences and Ethics Committee with the file number IR.MUK.REC.1399.087.
Consent for publication
Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article which was approved by the Research Center of Kurdistan University of Medical Sciences.
Competing interests
All authors declare that there is no conflict of interest that prejudices the impartiality of this scientific work.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ASPIRIN, CYANOCOBALAMIN\PYRIDOXINE\THIAMINE, FAMOTIDINE, HEPARIN SODIUM, HYDROXYCHLOROQUINE, NAPROXEN, ZINC | DrugsGivenReaction | CC BY | 33658082 | 20,204,296 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxic skin eruption'. | Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole.
Skeletal involvement of Cryptococcus neoformans is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient.
We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations.
To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.
Case Report
A 42-year-old male from Pakistan was admitted to hospital in July 2018 complaining of chronic lumbar pain. The patient, who had been living in Barcelona since 2003, was recently diagnosed with type 2 diabetes mellitus, established with two hemoglobin A1C tests of over 6.5%, and was well controlled on diet. He had no other medical conditions. He worked in public works water and sewer maintenance and claimed to have had no prior contact with animals. The patient reported a 6-month history of mechanical lumbar pain, without any previous trauma. The only symptoms reported during this time were 5 kg weight loss and 24-hr fever. After five months of pain, nodular lesions in the right gluteal region were noticed and antibiotic treatment was initiated by his general practitioner (amoxicillin-clavulanate 1g/200mg TID for 10 days and thereafter ciprofloxacin 500 mg BID for 10 days). Despite antibiotic treatment, pain and inflammatory signs increased and spontaneous drainage of the gluteal abscess occurred. A sample was taken for microbiological cultures and Cryptococcus neoformans was isolated. The patient was hospitalized for further study. Physical examination at admission revealed two indurated areas without inflammatory signs in the right gluteus and right lumbar area. The rest of the exploration was unremarkable. Laboratory tests showed renal and liver function values within the normal range (total bilirubin 0.36 mg/dl, GOT 31 UI/L, GPT 29 UI/L, FA 67 UI/L), hemoglobin 15.3 g/dl, white cell count 6940 cells/µL (44.2% neutrophils, 44.5% lymphocyte). The plasma cryptococcal antigen latex agglutination test (CLAT) was positive (1:100), suggesting a disseminated infection. A lumbar puncture was performed with normal results, including a negative CLAT. Human immunodeficiency virus (HIV), primary immunodeficiencies and a lymphoproliferative disorder were ruled out. CD4 and CD8 counts were in the normal range. Except for diabetes, no other predisposing factors were found. Thoraco-abdominal computed tomography ruled out lung involvement and revealed a gluteal abscess and a 3 cm lytic lesion on the right iliac crest (Figure 1). An ultrasound-guided fine-needle aspiration biopsy of the iliac crest was performed. No further surgical debridement was performed. The sample was inoculated on Polyvitex and Sabouraud agar plates (Biomèrieux®) and incubated at 37°C. Growth was observed after 72h incubation and the strain was identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS, BrukerDaltonics®) as C. neoformans. Antifungal susceptibility testing was performed using the Sensititre YeastOne® method, showing susceptibility to fluconazole [minimum inhibitory concentration (MIC) of 2 mg/L] and amphotericin B.Figure 1 Transverse computed tomography image of the pelvis.
Notes: (A) Bone window: Osteolytic lesion with cortical bone destruction involving the right iliac bone (white arrow). (B) Soft tissue window: bulking of the right iliac and gluteus medius muscle with an abscess in the latter (*).
Since the patient refused to remain in hospital due to family and work responsibilities, a treatment regimen was planned based on a single-dose of liposomal amphotericin B (L-AmB) (10 mg/kg, total dose 870 mg), infused over 3h, followed by outpatient therapy with oral fluconazole (800 mg/day). However, after the second dose of fluconazole, the patient developed a pruritic erythematous maculopapular rash. Given the lack of alternatives due to his personal circumstances and based on previous data in patients without HIV,1 a rapid oral desensitization protocol was performed (Table 1). Desensitization was conducted over 8 hours without complications, and the patient was discharged afterwards. He received 800 mg fluconazole daily for 14 days, followed by 400mg daily for one year. The treatment was well tolerated with no adverse events. The pain resolved and plasma CLAT was undetectable at the end of treatment. During follow-up, on-site monitoring of fluconazole blood concentrations was conducted. While patient was on 800 mg, the area under the curve (AUC)/MIC was 420 (objective >389). With the later 400 mg dosage, a further 3 samples were obtained, yielding AUC/MICs of 144, 180 and 156 (goal >100). At the end of follow-up, a mild alteration in liver function was observed (total bilirubin 0.24 mg/dl, AST 41 UI/L, ALT 45 UI/L, GGT 62 UI/L and FA 67 UI/L), which was attributable to moderate liver steatosis confirmed by abdominal echography. After 20 months of follow-up, the patient continued asymptomatic without signs of recurrence.Table 1 Protocol of Fluconazole Desensitization
Step Fluconazole Dilution (mg/mL) Volume Administered (mL) Fluconazole Dose (mg) Cumulative Dose
1 0.002 10 0.02 0.02
2 0.005 10 0.05 0.07
3 0.01 10 0.1 0.17
4 0.02 10 0.2 0.37
5 0.04 10 0.4 0.77
6 0.08 10 0.8 1.57
7 0.16 10 1.6 3.17
8 2.0 5 4 7.17
9 2.0 3.13 6.25 13.42
10 2.0 6.25 12.5 25.92
11 2.0 12.5 25 50.92
12 2.0 25 50 100.92
13 2.0 50 100 200.92
14 – – 200 400.92
15 – – 400 800.92
16 – – 800 1600.92
Note: A time interval of 30 minutes between doses was established.
Discussion
C. neoformans is a yeast normally found in soil. It causes opportunistic infection in immunocompromised patients, typically those with acquired immune deficiency syndrome.2 Although localized pulmonary disease is the main primary infection, extrapulmonary disease is common; especially central nervous system (CNS) infection.3 Osteoarticular cryptococcosis as the sole manifestation of extrapulmonary disease is rare, with an incidence of 5% in patients with cryptococcal disease.3 Hematogenous dissemination after the primary pulmonary infection may explain bone affectation.3 All of these findings are even rarer in immunocompetent patients.4 In our case, diabetes mellitus was the only risk factor predisposing to cryptococcal infection. An exhaustive study ruled out other immunodeficiencies. Although diabetes mellitus is a known risk factor for fungal infection, our patient had non-severe diabetes, with glucose levels well controlled by diet. We, therefore, considered low-grade immunosuppression due to diabetes. The patient also denied exposure to other risk factors, such as avian guano. While exceptional, other cases of cryptococcal infection with osteoarticular involvement in seemingly healthy patients have been reported.3–8
Little is known about the optimal treatment of osteoarticular cryptococcosis. Most cases reported in the literature propose a wide variety of treatments, based on antifungal drug therapy and surgical debridement.3,5 In contrast, more evidence is available for the management of CNS infection. Recently, a Phase 2 non-inferiority clinical trial in HIV-associated cryptococcal meningitis showed that a single high-dose of L-AmB plus high-dose oral fluconazole was non-inferior to 14 days of 3 mg/kg/day L-AmB in clearing cerebrospinal fluid infection.9 In our case, although CNS infection was ruled out, high levels of cryptococcal antigen in blood suggested disseminated cryptococcal infection. Moreover, bone involvement requires high doses of antifungal agents due to its poor vasculature. Consequently, based on the latest IDSA guidelines10 and the evidence in CNS infection,11 we treated this case with induction therapy consisting of a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole for twelve months. Remarkably, we report a successful desensitization therapy that may be useful in other patients with fluconazole allergy. Throughout the entire course of fluconazole treatment, the plasma levels were considered therapeutic, since they achieved the recommended AUC/MIC of ≥389 in induction therapy and AUC/MIC ≥100 during consolidation therapy.12
In conclusion, we present an atypical case of bone and soft tissue cryptococcal infection in an immunocompetent host, which was managed with antifungal treatment without surgical debridement. Induction therapy with a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole appears to be effective. Fluconazole desensitization and therapeutic drug monitoring ensured the proper application of treatment for twelve months and suggests that results may be similarly effective when applied to other patients.
Abbreviations
L-AmB, liposomal amphotericin B; CNS, central nervous system; CLAT, cryptococcal antigen latex agglutination test; HIV, human immunodeficiency virus; MIC, minimum inhibitory concentration; AUC, area under the curve.
Data Sharing Statement
All data (image and table) used in this study are included in this published article. We do not have metadata sharing, thus, it is not applicable to this article.
Ethics Approval
No institutional approval was required to publish the case details.
Consent for Publication
The patient gave written informed consent to the publication of his history and photographs.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Juan Pablo Horcajada reports being a speaker with honoraria advisory boards for MSD, Pfizer, and Menarini. The authors report no conflicts of interest in this work. | AMPHOTERICIN B, FLUCONAZOLE | DrugsGivenReaction | CC BY-NC | 33658808 | 19,132,164 | 2021 |
What was the administration route of drug 'FLUCONAZOLE'? | Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole.
Skeletal involvement of Cryptococcus neoformans is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient.
We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations.
To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.
Case Report
A 42-year-old male from Pakistan was admitted to hospital in July 2018 complaining of chronic lumbar pain. The patient, who had been living in Barcelona since 2003, was recently diagnosed with type 2 diabetes mellitus, established with two hemoglobin A1C tests of over 6.5%, and was well controlled on diet. He had no other medical conditions. He worked in public works water and sewer maintenance and claimed to have had no prior contact with animals. The patient reported a 6-month history of mechanical lumbar pain, without any previous trauma. The only symptoms reported during this time were 5 kg weight loss and 24-hr fever. After five months of pain, nodular lesions in the right gluteal region were noticed and antibiotic treatment was initiated by his general practitioner (amoxicillin-clavulanate 1g/200mg TID for 10 days and thereafter ciprofloxacin 500 mg BID for 10 days). Despite antibiotic treatment, pain and inflammatory signs increased and spontaneous drainage of the gluteal abscess occurred. A sample was taken for microbiological cultures and Cryptococcus neoformans was isolated. The patient was hospitalized for further study. Physical examination at admission revealed two indurated areas without inflammatory signs in the right gluteus and right lumbar area. The rest of the exploration was unremarkable. Laboratory tests showed renal and liver function values within the normal range (total bilirubin 0.36 mg/dl, GOT 31 UI/L, GPT 29 UI/L, FA 67 UI/L), hemoglobin 15.3 g/dl, white cell count 6940 cells/µL (44.2% neutrophils, 44.5% lymphocyte). The plasma cryptococcal antigen latex agglutination test (CLAT) was positive (1:100), suggesting a disseminated infection. A lumbar puncture was performed with normal results, including a negative CLAT. Human immunodeficiency virus (HIV), primary immunodeficiencies and a lymphoproliferative disorder were ruled out. CD4 and CD8 counts were in the normal range. Except for diabetes, no other predisposing factors were found. Thoraco-abdominal computed tomography ruled out lung involvement and revealed a gluteal abscess and a 3 cm lytic lesion on the right iliac crest (Figure 1). An ultrasound-guided fine-needle aspiration biopsy of the iliac crest was performed. No further surgical debridement was performed. The sample was inoculated on Polyvitex and Sabouraud agar plates (Biomèrieux®) and incubated at 37°C. Growth was observed after 72h incubation and the strain was identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS, BrukerDaltonics®) as C. neoformans. Antifungal susceptibility testing was performed using the Sensititre YeastOne® method, showing susceptibility to fluconazole [minimum inhibitory concentration (MIC) of 2 mg/L] and amphotericin B.Figure 1 Transverse computed tomography image of the pelvis.
Notes: (A) Bone window: Osteolytic lesion with cortical bone destruction involving the right iliac bone (white arrow). (B) Soft tissue window: bulking of the right iliac and gluteus medius muscle with an abscess in the latter (*).
Since the patient refused to remain in hospital due to family and work responsibilities, a treatment regimen was planned based on a single-dose of liposomal amphotericin B (L-AmB) (10 mg/kg, total dose 870 mg), infused over 3h, followed by outpatient therapy with oral fluconazole (800 mg/day). However, after the second dose of fluconazole, the patient developed a pruritic erythematous maculopapular rash. Given the lack of alternatives due to his personal circumstances and based on previous data in patients without HIV,1 a rapid oral desensitization protocol was performed (Table 1). Desensitization was conducted over 8 hours without complications, and the patient was discharged afterwards. He received 800 mg fluconazole daily for 14 days, followed by 400mg daily for one year. The treatment was well tolerated with no adverse events. The pain resolved and plasma CLAT was undetectable at the end of treatment. During follow-up, on-site monitoring of fluconazole blood concentrations was conducted. While patient was on 800 mg, the area under the curve (AUC)/MIC was 420 (objective >389). With the later 400 mg dosage, a further 3 samples were obtained, yielding AUC/MICs of 144, 180 and 156 (goal >100). At the end of follow-up, a mild alteration in liver function was observed (total bilirubin 0.24 mg/dl, AST 41 UI/L, ALT 45 UI/L, GGT 62 UI/L and FA 67 UI/L), which was attributable to moderate liver steatosis confirmed by abdominal echography. After 20 months of follow-up, the patient continued asymptomatic without signs of recurrence.Table 1 Protocol of Fluconazole Desensitization
Step Fluconazole Dilution (mg/mL) Volume Administered (mL) Fluconazole Dose (mg) Cumulative Dose
1 0.002 10 0.02 0.02
2 0.005 10 0.05 0.07
3 0.01 10 0.1 0.17
4 0.02 10 0.2 0.37
5 0.04 10 0.4 0.77
6 0.08 10 0.8 1.57
7 0.16 10 1.6 3.17
8 2.0 5 4 7.17
9 2.0 3.13 6.25 13.42
10 2.0 6.25 12.5 25.92
11 2.0 12.5 25 50.92
12 2.0 25 50 100.92
13 2.0 50 100 200.92
14 – – 200 400.92
15 – – 400 800.92
16 – – 800 1600.92
Note: A time interval of 30 minutes between doses was established.
Discussion
C. neoformans is a yeast normally found in soil. It causes opportunistic infection in immunocompromised patients, typically those with acquired immune deficiency syndrome.2 Although localized pulmonary disease is the main primary infection, extrapulmonary disease is common; especially central nervous system (CNS) infection.3 Osteoarticular cryptococcosis as the sole manifestation of extrapulmonary disease is rare, with an incidence of 5% in patients with cryptococcal disease.3 Hematogenous dissemination after the primary pulmonary infection may explain bone affectation.3 All of these findings are even rarer in immunocompetent patients.4 In our case, diabetes mellitus was the only risk factor predisposing to cryptococcal infection. An exhaustive study ruled out other immunodeficiencies. Although diabetes mellitus is a known risk factor for fungal infection, our patient had non-severe diabetes, with glucose levels well controlled by diet. We, therefore, considered low-grade immunosuppression due to diabetes. The patient also denied exposure to other risk factors, such as avian guano. While exceptional, other cases of cryptococcal infection with osteoarticular involvement in seemingly healthy patients have been reported.3–8
Little is known about the optimal treatment of osteoarticular cryptococcosis. Most cases reported in the literature propose a wide variety of treatments, based on antifungal drug therapy and surgical debridement.3,5 In contrast, more evidence is available for the management of CNS infection. Recently, a Phase 2 non-inferiority clinical trial in HIV-associated cryptococcal meningitis showed that a single high-dose of L-AmB plus high-dose oral fluconazole was non-inferior to 14 days of 3 mg/kg/day L-AmB in clearing cerebrospinal fluid infection.9 In our case, although CNS infection was ruled out, high levels of cryptococcal antigen in blood suggested disseminated cryptococcal infection. Moreover, bone involvement requires high doses of antifungal agents due to its poor vasculature. Consequently, based on the latest IDSA guidelines10 and the evidence in CNS infection,11 we treated this case with induction therapy consisting of a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole for twelve months. Remarkably, we report a successful desensitization therapy that may be useful in other patients with fluconazole allergy. Throughout the entire course of fluconazole treatment, the plasma levels were considered therapeutic, since they achieved the recommended AUC/MIC of ≥389 in induction therapy and AUC/MIC ≥100 during consolidation therapy.12
In conclusion, we present an atypical case of bone and soft tissue cryptococcal infection in an immunocompetent host, which was managed with antifungal treatment without surgical debridement. Induction therapy with a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole appears to be effective. Fluconazole desensitization and therapeutic drug monitoring ensured the proper application of treatment for twelve months and suggests that results may be similarly effective when applied to other patients.
Abbreviations
L-AmB, liposomal amphotericin B; CNS, central nervous system; CLAT, cryptococcal antigen latex agglutination test; HIV, human immunodeficiency virus; MIC, minimum inhibitory concentration; AUC, area under the curve.
Data Sharing Statement
All data (image and table) used in this study are included in this published article. We do not have metadata sharing, thus, it is not applicable to this article.
Ethics Approval
No institutional approval was required to publish the case details.
Consent for Publication
The patient gave written informed consent to the publication of his history and photographs.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Juan Pablo Horcajada reports being a speaker with honoraria advisory boards for MSD, Pfizer, and Menarini. The authors report no conflicts of interest in this work. | Oral | DrugAdministrationRoute | CC BY-NC | 33658808 | 19,132,164 | 2021 |
What was the dosage of drug 'AMPHOTERICIN B'? | Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole.
Skeletal involvement of Cryptococcus neoformans is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient.
We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations.
To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.
Case Report
A 42-year-old male from Pakistan was admitted to hospital in July 2018 complaining of chronic lumbar pain. The patient, who had been living in Barcelona since 2003, was recently diagnosed with type 2 diabetes mellitus, established with two hemoglobin A1C tests of over 6.5%, and was well controlled on diet. He had no other medical conditions. He worked in public works water and sewer maintenance and claimed to have had no prior contact with animals. The patient reported a 6-month history of mechanical lumbar pain, without any previous trauma. The only symptoms reported during this time were 5 kg weight loss and 24-hr fever. After five months of pain, nodular lesions in the right gluteal region were noticed and antibiotic treatment was initiated by his general practitioner (amoxicillin-clavulanate 1g/200mg TID for 10 days and thereafter ciprofloxacin 500 mg BID for 10 days). Despite antibiotic treatment, pain and inflammatory signs increased and spontaneous drainage of the gluteal abscess occurred. A sample was taken for microbiological cultures and Cryptococcus neoformans was isolated. The patient was hospitalized for further study. Physical examination at admission revealed two indurated areas without inflammatory signs in the right gluteus and right lumbar area. The rest of the exploration was unremarkable. Laboratory tests showed renal and liver function values within the normal range (total bilirubin 0.36 mg/dl, GOT 31 UI/L, GPT 29 UI/L, FA 67 UI/L), hemoglobin 15.3 g/dl, white cell count 6940 cells/µL (44.2% neutrophils, 44.5% lymphocyte). The plasma cryptococcal antigen latex agglutination test (CLAT) was positive (1:100), suggesting a disseminated infection. A lumbar puncture was performed with normal results, including a negative CLAT. Human immunodeficiency virus (HIV), primary immunodeficiencies and a lymphoproliferative disorder were ruled out. CD4 and CD8 counts were in the normal range. Except for diabetes, no other predisposing factors were found. Thoraco-abdominal computed tomography ruled out lung involvement and revealed a gluteal abscess and a 3 cm lytic lesion on the right iliac crest (Figure 1). An ultrasound-guided fine-needle aspiration biopsy of the iliac crest was performed. No further surgical debridement was performed. The sample was inoculated on Polyvitex and Sabouraud agar plates (Biomèrieux®) and incubated at 37°C. Growth was observed after 72h incubation and the strain was identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS, BrukerDaltonics®) as C. neoformans. Antifungal susceptibility testing was performed using the Sensititre YeastOne® method, showing susceptibility to fluconazole [minimum inhibitory concentration (MIC) of 2 mg/L] and amphotericin B.Figure 1 Transverse computed tomography image of the pelvis.
Notes: (A) Bone window: Osteolytic lesion with cortical bone destruction involving the right iliac bone (white arrow). (B) Soft tissue window: bulking of the right iliac and gluteus medius muscle with an abscess in the latter (*).
Since the patient refused to remain in hospital due to family and work responsibilities, a treatment regimen was planned based on a single-dose of liposomal amphotericin B (L-AmB) (10 mg/kg, total dose 870 mg), infused over 3h, followed by outpatient therapy with oral fluconazole (800 mg/day). However, after the second dose of fluconazole, the patient developed a pruritic erythematous maculopapular rash. Given the lack of alternatives due to his personal circumstances and based on previous data in patients without HIV,1 a rapid oral desensitization protocol was performed (Table 1). Desensitization was conducted over 8 hours without complications, and the patient was discharged afterwards. He received 800 mg fluconazole daily for 14 days, followed by 400mg daily for one year. The treatment was well tolerated with no adverse events. The pain resolved and plasma CLAT was undetectable at the end of treatment. During follow-up, on-site monitoring of fluconazole blood concentrations was conducted. While patient was on 800 mg, the area under the curve (AUC)/MIC was 420 (objective >389). With the later 400 mg dosage, a further 3 samples were obtained, yielding AUC/MICs of 144, 180 and 156 (goal >100). At the end of follow-up, a mild alteration in liver function was observed (total bilirubin 0.24 mg/dl, AST 41 UI/L, ALT 45 UI/L, GGT 62 UI/L and FA 67 UI/L), which was attributable to moderate liver steatosis confirmed by abdominal echography. After 20 months of follow-up, the patient continued asymptomatic without signs of recurrence.Table 1 Protocol of Fluconazole Desensitization
Step Fluconazole Dilution (mg/mL) Volume Administered (mL) Fluconazole Dose (mg) Cumulative Dose
1 0.002 10 0.02 0.02
2 0.005 10 0.05 0.07
3 0.01 10 0.1 0.17
4 0.02 10 0.2 0.37
5 0.04 10 0.4 0.77
6 0.08 10 0.8 1.57
7 0.16 10 1.6 3.17
8 2.0 5 4 7.17
9 2.0 3.13 6.25 13.42
10 2.0 6.25 12.5 25.92
11 2.0 12.5 25 50.92
12 2.0 25 50 100.92
13 2.0 50 100 200.92
14 – – 200 400.92
15 – – 400 800.92
16 – – 800 1600.92
Note: A time interval of 30 minutes between doses was established.
Discussion
C. neoformans is a yeast normally found in soil. It causes opportunistic infection in immunocompromised patients, typically those with acquired immune deficiency syndrome.2 Although localized pulmonary disease is the main primary infection, extrapulmonary disease is common; especially central nervous system (CNS) infection.3 Osteoarticular cryptococcosis as the sole manifestation of extrapulmonary disease is rare, with an incidence of 5% in patients with cryptococcal disease.3 Hematogenous dissemination after the primary pulmonary infection may explain bone affectation.3 All of these findings are even rarer in immunocompetent patients.4 In our case, diabetes mellitus was the only risk factor predisposing to cryptococcal infection. An exhaustive study ruled out other immunodeficiencies. Although diabetes mellitus is a known risk factor for fungal infection, our patient had non-severe diabetes, with glucose levels well controlled by diet. We, therefore, considered low-grade immunosuppression due to diabetes. The patient also denied exposure to other risk factors, such as avian guano. While exceptional, other cases of cryptococcal infection with osteoarticular involvement in seemingly healthy patients have been reported.3–8
Little is known about the optimal treatment of osteoarticular cryptococcosis. Most cases reported in the literature propose a wide variety of treatments, based on antifungal drug therapy and surgical debridement.3,5 In contrast, more evidence is available for the management of CNS infection. Recently, a Phase 2 non-inferiority clinical trial in HIV-associated cryptococcal meningitis showed that a single high-dose of L-AmB plus high-dose oral fluconazole was non-inferior to 14 days of 3 mg/kg/day L-AmB in clearing cerebrospinal fluid infection.9 In our case, although CNS infection was ruled out, high levels of cryptococcal antigen in blood suggested disseminated cryptococcal infection. Moreover, bone involvement requires high doses of antifungal agents due to its poor vasculature. Consequently, based on the latest IDSA guidelines10 and the evidence in CNS infection,11 we treated this case with induction therapy consisting of a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole for twelve months. Remarkably, we report a successful desensitization therapy that may be useful in other patients with fluconazole allergy. Throughout the entire course of fluconazole treatment, the plasma levels were considered therapeutic, since they achieved the recommended AUC/MIC of ≥389 in induction therapy and AUC/MIC ≥100 during consolidation therapy.12
In conclusion, we present an atypical case of bone and soft tissue cryptococcal infection in an immunocompetent host, which was managed with antifungal treatment without surgical debridement. Induction therapy with a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole appears to be effective. Fluconazole desensitization and therapeutic drug monitoring ensured the proper application of treatment for twelve months and suggests that results may be similarly effective when applied to other patients.
Abbreviations
L-AmB, liposomal amphotericin B; CNS, central nervous system; CLAT, cryptococcal antigen latex agglutination test; HIV, human immunodeficiency virus; MIC, minimum inhibitory concentration; AUC, area under the curve.
Data Sharing Statement
All data (image and table) used in this study are included in this published article. We do not have metadata sharing, thus, it is not applicable to this article.
Ethics Approval
No institutional approval was required to publish the case details.
Consent for Publication
The patient gave written informed consent to the publication of his history and photographs.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Juan Pablo Horcajada reports being a speaker with honoraria advisory boards for MSD, Pfizer, and Menarini. The authors report no conflicts of interest in this work. | TOTAL DOSE 870MG INFUSED OVER 3H | DrugDosageText | CC BY-NC | 33658808 | 19,132,164 | 2021 |
What was the dosage of drug 'FLUCONAZOLE'? | Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole.
Skeletal involvement of Cryptococcus neoformans is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient.
We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations.
To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.
Case Report
A 42-year-old male from Pakistan was admitted to hospital in July 2018 complaining of chronic lumbar pain. The patient, who had been living in Barcelona since 2003, was recently diagnosed with type 2 diabetes mellitus, established with two hemoglobin A1C tests of over 6.5%, and was well controlled on diet. He had no other medical conditions. He worked in public works water and sewer maintenance and claimed to have had no prior contact with animals. The patient reported a 6-month history of mechanical lumbar pain, without any previous trauma. The only symptoms reported during this time were 5 kg weight loss and 24-hr fever. After five months of pain, nodular lesions in the right gluteal region were noticed and antibiotic treatment was initiated by his general practitioner (amoxicillin-clavulanate 1g/200mg TID for 10 days and thereafter ciprofloxacin 500 mg BID for 10 days). Despite antibiotic treatment, pain and inflammatory signs increased and spontaneous drainage of the gluteal abscess occurred. A sample was taken for microbiological cultures and Cryptococcus neoformans was isolated. The patient was hospitalized for further study. Physical examination at admission revealed two indurated areas without inflammatory signs in the right gluteus and right lumbar area. The rest of the exploration was unremarkable. Laboratory tests showed renal and liver function values within the normal range (total bilirubin 0.36 mg/dl, GOT 31 UI/L, GPT 29 UI/L, FA 67 UI/L), hemoglobin 15.3 g/dl, white cell count 6940 cells/µL (44.2% neutrophils, 44.5% lymphocyte). The plasma cryptococcal antigen latex agglutination test (CLAT) was positive (1:100), suggesting a disseminated infection. A lumbar puncture was performed with normal results, including a negative CLAT. Human immunodeficiency virus (HIV), primary immunodeficiencies and a lymphoproliferative disorder were ruled out. CD4 and CD8 counts were in the normal range. Except for diabetes, no other predisposing factors were found. Thoraco-abdominal computed tomography ruled out lung involvement and revealed a gluteal abscess and a 3 cm lytic lesion on the right iliac crest (Figure 1). An ultrasound-guided fine-needle aspiration biopsy of the iliac crest was performed. No further surgical debridement was performed. The sample was inoculated on Polyvitex and Sabouraud agar plates (Biomèrieux®) and incubated at 37°C. Growth was observed after 72h incubation and the strain was identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS, BrukerDaltonics®) as C. neoformans. Antifungal susceptibility testing was performed using the Sensititre YeastOne® method, showing susceptibility to fluconazole [minimum inhibitory concentration (MIC) of 2 mg/L] and amphotericin B.Figure 1 Transverse computed tomography image of the pelvis.
Notes: (A) Bone window: Osteolytic lesion with cortical bone destruction involving the right iliac bone (white arrow). (B) Soft tissue window: bulking of the right iliac and gluteus medius muscle with an abscess in the latter (*).
Since the patient refused to remain in hospital due to family and work responsibilities, a treatment regimen was planned based on a single-dose of liposomal amphotericin B (L-AmB) (10 mg/kg, total dose 870 mg), infused over 3h, followed by outpatient therapy with oral fluconazole (800 mg/day). However, after the second dose of fluconazole, the patient developed a pruritic erythematous maculopapular rash. Given the lack of alternatives due to his personal circumstances and based on previous data in patients without HIV,1 a rapid oral desensitization protocol was performed (Table 1). Desensitization was conducted over 8 hours without complications, and the patient was discharged afterwards. He received 800 mg fluconazole daily for 14 days, followed by 400mg daily for one year. The treatment was well tolerated with no adverse events. The pain resolved and plasma CLAT was undetectable at the end of treatment. During follow-up, on-site monitoring of fluconazole blood concentrations was conducted. While patient was on 800 mg, the area under the curve (AUC)/MIC was 420 (objective >389). With the later 400 mg dosage, a further 3 samples were obtained, yielding AUC/MICs of 144, 180 and 156 (goal >100). At the end of follow-up, a mild alteration in liver function was observed (total bilirubin 0.24 mg/dl, AST 41 UI/L, ALT 45 UI/L, GGT 62 UI/L and FA 67 UI/L), which was attributable to moderate liver steatosis confirmed by abdominal echography. After 20 months of follow-up, the patient continued asymptomatic without signs of recurrence.Table 1 Protocol of Fluconazole Desensitization
Step Fluconazole Dilution (mg/mL) Volume Administered (mL) Fluconazole Dose (mg) Cumulative Dose
1 0.002 10 0.02 0.02
2 0.005 10 0.05 0.07
3 0.01 10 0.1 0.17
4 0.02 10 0.2 0.37
5 0.04 10 0.4 0.77
6 0.08 10 0.8 1.57
7 0.16 10 1.6 3.17
8 2.0 5 4 7.17
9 2.0 3.13 6.25 13.42
10 2.0 6.25 12.5 25.92
11 2.0 12.5 25 50.92
12 2.0 25 50 100.92
13 2.0 50 100 200.92
14 – – 200 400.92
15 – – 400 800.92
16 – – 800 1600.92
Note: A time interval of 30 minutes between doses was established.
Discussion
C. neoformans is a yeast normally found in soil. It causes opportunistic infection in immunocompromised patients, typically those with acquired immune deficiency syndrome.2 Although localized pulmonary disease is the main primary infection, extrapulmonary disease is common; especially central nervous system (CNS) infection.3 Osteoarticular cryptococcosis as the sole manifestation of extrapulmonary disease is rare, with an incidence of 5% in patients with cryptococcal disease.3 Hematogenous dissemination after the primary pulmonary infection may explain bone affectation.3 All of these findings are even rarer in immunocompetent patients.4 In our case, diabetes mellitus was the only risk factor predisposing to cryptococcal infection. An exhaustive study ruled out other immunodeficiencies. Although diabetes mellitus is a known risk factor for fungal infection, our patient had non-severe diabetes, with glucose levels well controlled by diet. We, therefore, considered low-grade immunosuppression due to diabetes. The patient also denied exposure to other risk factors, such as avian guano. While exceptional, other cases of cryptococcal infection with osteoarticular involvement in seemingly healthy patients have been reported.3–8
Little is known about the optimal treatment of osteoarticular cryptococcosis. Most cases reported in the literature propose a wide variety of treatments, based on antifungal drug therapy and surgical debridement.3,5 In contrast, more evidence is available for the management of CNS infection. Recently, a Phase 2 non-inferiority clinical trial in HIV-associated cryptococcal meningitis showed that a single high-dose of L-AmB plus high-dose oral fluconazole was non-inferior to 14 days of 3 mg/kg/day L-AmB in clearing cerebrospinal fluid infection.9 In our case, although CNS infection was ruled out, high levels of cryptococcal antigen in blood suggested disseminated cryptococcal infection. Moreover, bone involvement requires high doses of antifungal agents due to its poor vasculature. Consequently, based on the latest IDSA guidelines10 and the evidence in CNS infection,11 we treated this case with induction therapy consisting of a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole for twelve months. Remarkably, we report a successful desensitization therapy that may be useful in other patients with fluconazole allergy. Throughout the entire course of fluconazole treatment, the plasma levels were considered therapeutic, since they achieved the recommended AUC/MIC of ≥389 in induction therapy and AUC/MIC ≥100 during consolidation therapy.12
In conclusion, we present an atypical case of bone and soft tissue cryptococcal infection in an immunocompetent host, which was managed with antifungal treatment without surgical debridement. Induction therapy with a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole appears to be effective. Fluconazole desensitization and therapeutic drug monitoring ensured the proper application of treatment for twelve months and suggests that results may be similarly effective when applied to other patients.
Abbreviations
L-AmB, liposomal amphotericin B; CNS, central nervous system; CLAT, cryptococcal antigen latex agglutination test; HIV, human immunodeficiency virus; MIC, minimum inhibitory concentration; AUC, area under the curve.
Data Sharing Statement
All data (image and table) used in this study are included in this published article. We do not have metadata sharing, thus, it is not applicable to this article.
Ethics Approval
No institutional approval was required to publish the case details.
Consent for Publication
The patient gave written informed consent to the publication of his history and photographs.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Juan Pablo Horcajada reports being a speaker with honoraria advisory boards for MSD, Pfizer, and Menarini. The authors report no conflicts of interest in this work. | 800 MILLIGRAM DAILY; | DrugDosageText | CC BY-NC | 33658808 | 19,132,164 | 2021 |
What was the outcome of reaction 'Toxic skin eruption'? | Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole.
Skeletal involvement of Cryptococcus neoformans is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient.
We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations.
To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.
Case Report
A 42-year-old male from Pakistan was admitted to hospital in July 2018 complaining of chronic lumbar pain. The patient, who had been living in Barcelona since 2003, was recently diagnosed with type 2 diabetes mellitus, established with two hemoglobin A1C tests of over 6.5%, and was well controlled on diet. He had no other medical conditions. He worked in public works water and sewer maintenance and claimed to have had no prior contact with animals. The patient reported a 6-month history of mechanical lumbar pain, without any previous trauma. The only symptoms reported during this time were 5 kg weight loss and 24-hr fever. After five months of pain, nodular lesions in the right gluteal region were noticed and antibiotic treatment was initiated by his general practitioner (amoxicillin-clavulanate 1g/200mg TID for 10 days and thereafter ciprofloxacin 500 mg BID for 10 days). Despite antibiotic treatment, pain and inflammatory signs increased and spontaneous drainage of the gluteal abscess occurred. A sample was taken for microbiological cultures and Cryptococcus neoformans was isolated. The patient was hospitalized for further study. Physical examination at admission revealed two indurated areas without inflammatory signs in the right gluteus and right lumbar area. The rest of the exploration was unremarkable. Laboratory tests showed renal and liver function values within the normal range (total bilirubin 0.36 mg/dl, GOT 31 UI/L, GPT 29 UI/L, FA 67 UI/L), hemoglobin 15.3 g/dl, white cell count 6940 cells/µL (44.2% neutrophils, 44.5% lymphocyte). The plasma cryptococcal antigen latex agglutination test (CLAT) was positive (1:100), suggesting a disseminated infection. A lumbar puncture was performed with normal results, including a negative CLAT. Human immunodeficiency virus (HIV), primary immunodeficiencies and a lymphoproliferative disorder were ruled out. CD4 and CD8 counts were in the normal range. Except for diabetes, no other predisposing factors were found. Thoraco-abdominal computed tomography ruled out lung involvement and revealed a gluteal abscess and a 3 cm lytic lesion on the right iliac crest (Figure 1). An ultrasound-guided fine-needle aspiration biopsy of the iliac crest was performed. No further surgical debridement was performed. The sample was inoculated on Polyvitex and Sabouraud agar plates (Biomèrieux®) and incubated at 37°C. Growth was observed after 72h incubation and the strain was identified by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS, BrukerDaltonics®) as C. neoformans. Antifungal susceptibility testing was performed using the Sensititre YeastOne® method, showing susceptibility to fluconazole [minimum inhibitory concentration (MIC) of 2 mg/L] and amphotericin B.Figure 1 Transverse computed tomography image of the pelvis.
Notes: (A) Bone window: Osteolytic lesion with cortical bone destruction involving the right iliac bone (white arrow). (B) Soft tissue window: bulking of the right iliac and gluteus medius muscle with an abscess in the latter (*).
Since the patient refused to remain in hospital due to family and work responsibilities, a treatment regimen was planned based on a single-dose of liposomal amphotericin B (L-AmB) (10 mg/kg, total dose 870 mg), infused over 3h, followed by outpatient therapy with oral fluconazole (800 mg/day). However, after the second dose of fluconazole, the patient developed a pruritic erythematous maculopapular rash. Given the lack of alternatives due to his personal circumstances and based on previous data in patients without HIV,1 a rapid oral desensitization protocol was performed (Table 1). Desensitization was conducted over 8 hours without complications, and the patient was discharged afterwards. He received 800 mg fluconazole daily for 14 days, followed by 400mg daily for one year. The treatment was well tolerated with no adverse events. The pain resolved and plasma CLAT was undetectable at the end of treatment. During follow-up, on-site monitoring of fluconazole blood concentrations was conducted. While patient was on 800 mg, the area under the curve (AUC)/MIC was 420 (objective >389). With the later 400 mg dosage, a further 3 samples were obtained, yielding AUC/MICs of 144, 180 and 156 (goal >100). At the end of follow-up, a mild alteration in liver function was observed (total bilirubin 0.24 mg/dl, AST 41 UI/L, ALT 45 UI/L, GGT 62 UI/L and FA 67 UI/L), which was attributable to moderate liver steatosis confirmed by abdominal echography. After 20 months of follow-up, the patient continued asymptomatic without signs of recurrence.Table 1 Protocol of Fluconazole Desensitization
Step Fluconazole Dilution (mg/mL) Volume Administered (mL) Fluconazole Dose (mg) Cumulative Dose
1 0.002 10 0.02 0.02
2 0.005 10 0.05 0.07
3 0.01 10 0.1 0.17
4 0.02 10 0.2 0.37
5 0.04 10 0.4 0.77
6 0.08 10 0.8 1.57
7 0.16 10 1.6 3.17
8 2.0 5 4 7.17
9 2.0 3.13 6.25 13.42
10 2.0 6.25 12.5 25.92
11 2.0 12.5 25 50.92
12 2.0 25 50 100.92
13 2.0 50 100 200.92
14 – – 200 400.92
15 – – 400 800.92
16 – – 800 1600.92
Note: A time interval of 30 minutes between doses was established.
Discussion
C. neoformans is a yeast normally found in soil. It causes opportunistic infection in immunocompromised patients, typically those with acquired immune deficiency syndrome.2 Although localized pulmonary disease is the main primary infection, extrapulmonary disease is common; especially central nervous system (CNS) infection.3 Osteoarticular cryptococcosis as the sole manifestation of extrapulmonary disease is rare, with an incidence of 5% in patients with cryptococcal disease.3 Hematogenous dissemination after the primary pulmonary infection may explain bone affectation.3 All of these findings are even rarer in immunocompetent patients.4 In our case, diabetes mellitus was the only risk factor predisposing to cryptococcal infection. An exhaustive study ruled out other immunodeficiencies. Although diabetes mellitus is a known risk factor for fungal infection, our patient had non-severe diabetes, with glucose levels well controlled by diet. We, therefore, considered low-grade immunosuppression due to diabetes. The patient also denied exposure to other risk factors, such as avian guano. While exceptional, other cases of cryptococcal infection with osteoarticular involvement in seemingly healthy patients have been reported.3–8
Little is known about the optimal treatment of osteoarticular cryptococcosis. Most cases reported in the literature propose a wide variety of treatments, based on antifungal drug therapy and surgical debridement.3,5 In contrast, more evidence is available for the management of CNS infection. Recently, a Phase 2 non-inferiority clinical trial in HIV-associated cryptococcal meningitis showed that a single high-dose of L-AmB plus high-dose oral fluconazole was non-inferior to 14 days of 3 mg/kg/day L-AmB in clearing cerebrospinal fluid infection.9 In our case, although CNS infection was ruled out, high levels of cryptococcal antigen in blood suggested disseminated cryptococcal infection. Moreover, bone involvement requires high doses of antifungal agents due to its poor vasculature. Consequently, based on the latest IDSA guidelines10 and the evidence in CNS infection,11 we treated this case with induction therapy consisting of a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole for twelve months. Remarkably, we report a successful desensitization therapy that may be useful in other patients with fluconazole allergy. Throughout the entire course of fluconazole treatment, the plasma levels were considered therapeutic, since they achieved the recommended AUC/MIC of ≥389 in induction therapy and AUC/MIC ≥100 during consolidation therapy.12
In conclusion, we present an atypical case of bone and soft tissue cryptococcal infection in an immunocompetent host, which was managed with antifungal treatment without surgical debridement. Induction therapy with a single high-dose of L-AmB followed by maintenance treatment with oral fluconazole appears to be effective. Fluconazole desensitization and therapeutic drug monitoring ensured the proper application of treatment for twelve months and suggests that results may be similarly effective when applied to other patients.
Abbreviations
L-AmB, liposomal amphotericin B; CNS, central nervous system; CLAT, cryptococcal antigen latex agglutination test; HIV, human immunodeficiency virus; MIC, minimum inhibitory concentration; AUC, area under the curve.
Data Sharing Statement
All data (image and table) used in this study are included in this published article. We do not have metadata sharing, thus, it is not applicable to this article.
Ethics Approval
No institutional approval was required to publish the case details.
Consent for Publication
The patient gave written informed consent to the publication of his history and photographs.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Juan Pablo Horcajada reports being a speaker with honoraria advisory boards for MSD, Pfizer, and Menarini. The authors report no conflicts of interest in this work. | Recovered | ReactionOutcome | CC BY-NC | 33658808 | 19,132,164 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral ischaemia'. | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | ARIPIPRAZOLE, BUPRENORPHINE, NIMODIPINE, NOREPINEPHRINE, TUAMINOHEPTANE, VENLAFAXINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33658973 | 19,239,628 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | ARIPIPRAZOLE, BUPRENORPHINE, TUAMINOHEPTANE, VENLAFAXINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33658973 | 19,266,712 | 2021 |
What was the administration route of drug 'TUAMINOHEPTANE SULFATE'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Nasal | DrugAdministrationRoute | CC BY | 33658973 | 19,357,236 | 2021 |
What was the administration route of drug 'TUAMINOHEPTANE'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Nasal | DrugAdministrationRoute | CC BY | 33658973 | 19,239,628 | 2021 |
What was the outcome of reaction 'Brain herniation'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,239,628 | 2021 |
What was the outcome of reaction 'Brain oedema'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,357,236 | 2021 |
What was the outcome of reaction 'Coma'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,357,236 | 2021 |
What was the outcome of reaction 'Condition aggravated'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,357,236 | 2021 |
What was the outcome of reaction 'Drug interaction'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,266,712 | 2021 |
What was the outcome of reaction 'Haemorrhagic stroke'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,357,236 | 2021 |
What was the outcome of reaction 'Ischaemic stroke'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,357,236 | 2021 |
What was the outcome of reaction 'Reversible cerebral vasoconstriction syndrome'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,989,477 | 2021 |
What was the outcome of reaction 'Subarachnoid haemorrhage'? | Case Report and Review of the Literature: Fatal Reversible Cerebral Vasoconstriction Syndrome.
Background: A fatal outcome occurs in 2% of patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS). Due to its rarity, guidelines for the management of the most severe forms of RCVS are lacking. Case presentation: Here, we describe the case of a 55 year-old woman who died from complications of RCVS and reviewed patients with fatal outcome reported in the literature. In our patient, the first episode of neurological deterioration was preceded by an increase of cerebral blood flow velocities assessed with transcranial Doppler. A fatal evolution could not be prevented despite therapeutic escalation consisting of multiple non-invasive and invasive treatments including cervical sympathetic bloc and continuous arterial infusion of nimodipine at the site of severe vasoconstriction. Conclusion: This case and the review of literature illustrate the challenges in the management of patients with severe RCVS. We describe here how monitoring of cerebral blood flow might help anticipate clinical worsening at the beginning of the disease and propose novel invasive and non-invasive therapeutic strategies based on monitoring of neurophysiological parameters.
Introduction
The typical presentation of reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with or without acute neurological symptoms. Favorable outcome is reported in most case (1), although ischemic and hemorrhagic strokes can occur, leading to death in up to 2% of the cases (2). The therapeutic approach of patients suffering from severe RCVS remains a challenge for clinicians.
Here, we report the case of a patient with severe RCVS and fatal outcome and review the literature for similar patients. We investigated how monitoring of cerebral blood flow can help anticipate clinical worsening and propose novel invasive and non-invasive therapeutic strategies based on their impact neurophysiological data.
Methods
The systematic review of case reports/series of fatal RCVS used “pubmed” search to retrieve publications of patients with RCVS leading to death. Key words used included “reversible cerebral vasoconstriction syndrome” AND “death” (articles selected for the review/articles found on pubmed: 2/18); AND “fatal” (4/11); AND “fulminant” (5/8) AND “died” (5/25); AND “decease” (0/24); AND “poor outcome” (4/10). We excluded the four fatal cases mentioned in the retrospective observational study published by Katz et al. (3) (59 patients) because of the lack of information, especially regarding treatments.
Case Presentation
A 55-year-old woman experienced unusual recurrent episodes of thunderclap headaches (Day 0). The waxing and waning evolution caused the patient to trivialize the situation at initial stages. She was treated for bipolar disorder with aripiprazole and venlafaxine. The patient was smoking tetrahydrocannabinol (THC) regularly and benefited from long-term opioid substitution therapy (buprenorphine). Seven days before admission, she started using an over-the-counter nasal decongestant spray, including tuaminoheptane, a sympathomimetic vasoconstrictor.
On Day 4, she decided to consult at the emergency room of the closest hospital. Brain imaging by contrast CT (Day 4) and MRI (Day 4) showed a left parieto-occipital subarachnoid hemorrhage (SAH) (Figure 1). Cerebral vessels imaging by digital subtraction angiography (DSA, Day 5) evidenced widespread vasoconstrictions in proximal and distal arteries (Figure 2). That was not seen on initial MRA. Cerebrospinal fluid (CSF) analysis revealed high red blood cells (11'200/mm3), moderate elevation of protein level (0.94 g/L; <0.45) and normal white blood cells (0/mm3; <5). According to the international classification of headache disorders (ICHD3), we assumed the diagnosis of RCVS (4) and a calcium channel blocker therapy was started (nimodipine 30 mg tid orally). On Day 10, because of intracranial vasoconstrictions on transcranial Doppler (TCD) (mean cerebral blood flow velocities (mCBFV) in the right MCA at 200 cm/s and Lindegaard Index at 4.76), nimodipine was increased to 60 mg q.4h (Figure 3). On Day 11, the patient presented a left homonymous lateral hemianopsia (HLH) and fluctuant left upper limb paresis. Brain MRI showed acute border zone ischemic strokes (Figure 1).
Figure 1 Illustration of radiological brain lesions over time. (A) Left convexity subarachnoid hemorrhage (SAH) on Day 4 (non-contrast CT). (B) Brain parenchyma without damage next to the left convexity SAH on Day 4 [MRI, T2 Fluid Attenuated Inversion Recovery (FLAIR)]. (C) Brain parenchyma without damage on Day 4 [MRI, Diffusion Weighted Imaging (DWI)]. (D) Right watershed infarct at the border zone between right middle and posterior cerebral arteries on Day 11 at the time of first neurological deterioration (MRI, DWI). (E) Multiple hemodynamic strokes in supratentorial and infratentorial regions on Day 18 (MRI, DWI).
Figure 2 Illustration of cerebral digital subtraction angiographies (DSA) over time and response to treatments. (A) Cerebral Digital Subtraction Angiography (DSA) on Day 5 evidencing widespread arterial vasoconstrictions predominantly in brain distality (white arrow). (B) Cerebral DSA on Day 12 showing worsened distal and proximal (white arrow) arteries stenoses before intraarterial treatments. (C) Cerebral DSA on Day 12 showing distal and proximal (white arrow) arteries stenoses resolution after intraarterial injection of nimodipine and balloon angioplasty on proximal stenosis.
Figure 3 Evolution of physiological measures and effect of treatments. Evolution of mean arterial pressure (MAP), mean cerebral blood flow velocity (mCBFV), and Lindegaard index from Day 8 to 19. The three gray vertical bars indicate the episodes of clinical deterioration (Day 11, 13, 18).
Because of a decrease in mean arterial pressure (MAP) below 70 mmHg following nimodipine increase, the patient was admitted to the intensive care unit (Day 12). The therapeutic strategy aimed at increasing cerebral blood flow (CBF) with initiation of norepinephrine (MAP target 90–110 mmHg), and discontinuation of calcium channel blocker therapy to avoid vasodilatation with potential hypoperfusion. Elevation of mCBFV to 209 cm/s (Lindegaard Index 2.9) was found on Day 12, one day before new clinical worsening. Widespread acute bilateral ischemic lesions were found on NCCT and a second DSA revealed worsened bilateral proximal and distal arteries stenoses (Figure 2). Balloon angioplasty of the proximal MCA was performed, as well as intraarterial nimodipine administration, locally (Figure 2) and in both internal carotid arteries (Day 12, 14, 18, and 19), resulting in cerebral vasodilatation which however did not last after infusion cessation. Stellate ganglia bloc (level C6–C7) was performed on Day 14 (bupivacaine 0.5) with transient effects on vasoconstriction. On Day 17, persistent elevated mCBFV (202 cm/s) without significant change in Lindegaard Index (2.0) was observed hours before new clinical worsening. On Day 22, multiple cerebral ischemic and hemorrhagic strokes, as well as bi-hemispheric edema, were seen on NCCT. Because of the severity of the clinical examination (coma), the extent of brain lesions and limited additional therapies, a withholding therapy was considered after discussion with her relatives. The patient died on Day 23 due to brain herniation.
Ethics
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Discussion
Nasal vasoconstrictors, chronic use of THC and selective serotonin recapture inhibitor are all identified as potential RCVS triggers (5). Female gender and age of the patient at onset are also independent risk factors for RCVS (2). RCVS typically begins with distal arteriolar vasoconstriction with a centripetal course leading to normal and falsely reassuring TCD examination in the first days after onset. In our case, the monitoring of CBFV identified the development of proximal vasoconstriction at least several hours before neurological deterioration (Figure 3). The role of TCD to monitor cerebral vasospasm or delayed cerebral ischemia after aneurysmal SAH is currently debated (6, 7) but low or very high MCA CBFV (<120 or >200 cm/s) seem to reliably predict the absence or presence of clinically significant vasospasm (8, 9). The literature is more limited concerning the predictive value of TCD in patients with RCVS, which prevent to draw a conclusion about the role of TCD, especially because, in our case, none of the interventions based on TCD resulted in a positive outcome. Only a small case series of RCVS patients have been reported showing an increased CBFV in at least one major cerebral blood vessel (middle, anterior and posterior cerebral arteries, vertebral arteries, basilar artery) by initial TCD after RCVS diagnosis, and a peak MCA velocity reached 3–4 weeks after the onset of thunderclap headache (10). Chen et al. (11) demonstrated that MCA CBFV maintained a high plateau at the meantime of headache remission (Day 22) and remained abnormal even 10 days after headache resolution. TCD monitoring of RCVS patients may be difficult because the physiopathology of RCVS consists of the association of vasodilatation and vasoconstriction. Consequently, normal TCD could not rule out further RCVS aggravation. In our case, the elevation of CBFV preceded the development of proximal vasoconstriction at least several hours before the first ischemic stroke-related neurological deterioration (Figure 3). The prediction of the two other neurological deteriorations is not as clear possibly because TCD examinations were performed while the patient was admitted in the ICU under several vasoactive treatments (norepinephrine infusion, calcium channel blockers). The absence of continuous TCD monitoring limits further interpretations while RCVS is a dynamic process with permanent arterial caliber changes.
This case also illustrates the difficulties in treating the most severe cases of RCVS that might not be as “reversible” as this adjective suggests. As recommended by experts, we started with nimodipine therapy, initially orally then intravenously and finally using intraarterial in situ administration. Cerebral vasodilatation was demonstrated during local nimodipine administration (Figure 2), but the effects did not last after drug cessation. No validated guideline exists regarding doses of nimodipine. Even if the effect of nimodipine seems to be specific mainly to intracerebral arteries at low doses, higher intravenous doses also have a significant impact on systemic arterial blood pressure with a risk of developing cerebral hypoperfusion in patients with widespread vasospasms. Combination of systemic and local mechanisms may explain border zone ischemia that occurred in our patient when MAP dropped following increased doses of nimodipine. This therapy is more harmful at a later stage given the risk of bleeding in the already infarcted cerebral tissue due to reperfusion syndrome. As a second-line therapy, to increase CBF, hypertensive therapy was initiated with high doses of norepinephrine. Despite successful maintenance of MAP in the target range, clinical fluctuations were observed. A deleterious effect of norepinephrine cannot be ruled out as a cerebral vasoactive effect has been described although the vasoconstrictive effect of norepinephrine is mainly at the splanchnic and cutaneous levels (12). As a third line therapy, a balloon angioplasty and a bilateral stellate block (bupivacaine 0.5%) by analogy with previous reports in patients with vasospasm following SAH (13) were not associated with significant long term effect based on TCD monitoring. In the absence of evidence-based guidelines for this extremely rare situation, all the unsuccessful interventions failed to save patient life and raised the question of iatrogenicity. More data are needed to determine the benefits and the risks of this approach in severe cases of RCVS.
In the literature, death in the context of RCVS has been rarely reported (5). Table 1 summarizes previously described cases of RCVS with fatal outcome (14–27). RCVS occurrence peaks take place around 42-year-old, and the syndrome is more common in women than in men (5). Our fatal cases series seems to respect these data with a mean age of 41-year-old and 19 women out of 21 reported patients. Several potential causes of RCVS have been reported in patients with fatal RCVS that are similar those triggering more benign forms of RCVS (1), and these commonly known factors also trigger fatal RCVS (anti-depressive treatments, post-partum, THC consumption, nasal decongestant). Many of these cases (13/21) received steroids (methylprednisolone, prednisone, fludrocortisone) without positive effect. This observation is in line with recent comments suggesting glucocorticoid exposure as a contributing factor to worsening in RCVS (28, 29). Oral calcium channel blockers administration was initiated orally (but not intravenously) in 14/21 patients without favorable outcome. Second line therapies intended to improve global cerebral perfusion (norepinephrine or vasopressin to increase MAP) and third line interventional therapies (balloon angioplasty, stellate block) have only been used in, respectively, six and four cases out of 21, which limit definitive conclusions about their efficacy. Treatments reducing intracerebral pressure (osmotic therapy, hypothermia, fentanyl, and propofol) have been employed in rescue situations in patients with life-threatening cerebral complications (ischemic stroke, hemorrhagic stroke, cerebral edema).
Table 1 Baseline characteristics and treatments in our case and in the literature.
Population, disease and treatments characteristics Case Buckle et al. (14) Geraghty et al. (15) Williams et al. (16) Marshall et al. (17) Singhal et al. (18) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) Fugate et al. (19) John et al. (20) Robert et al. (21) Robert et al. (21) Thydén et al. (22) Sabzwari et al. (23) Suchdev et al. (24) Holanda Pena et al. (25) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26) Kunchok et al. (26)
Age 55 16 27 40 57 36 33 32 30 15 45 68 53 58 32 25 36 61 24 63 55
Gender F F F F F F F F F F F F F M F F F F M F F
Trigger Venlafaxine, THC,
tuaminoheptane None PP PP None PP PP PP PP PP Escitalopram,THC None THC None PP None PP Escitalopram THC Nasal decongestant Sertraline
Death delay after clinical onset (days) 23 2 21 14 25 28 25 18 14 7 21 4 13 7 12 21 36 28 21 14 42
First line therapies
Nimodipine X X X X X X X X X X X X
Nicardipine X X X
Verapamil X X X X X
Second line therapies
Norepinephrin X X X X
Vasopressin X X
Third line therapies
Balloon Angioplasty X X X X
Stellate bloc X
Other used therapies
Steroids: MP/P/fludrocort X X X X X X X X X X X X X
Cyclophosphamide X X X
Rituximab X
Immunoglobulins X
Labetalol X
Hypertonic therapy X X X X X X
Hypothermia X X
Fentanyl+propofol X
Magnesium X X X
Epoprostenol X
THC, tetrahydrocannabinol; F, female; M, male; PP, post-partum; fludrocort, fludrocortisone; MP, methylprednisolone; P, prednisone.
Our case has several limitations. First, because of the rapid deterioration of the patient's condition, we combined several treatments that may have acted synergistically or with opposite mechanisms. Therefore, the individual effect of each treatment is challenging to assess. Second, none of our therapeutic strategies resulted in a favorable outcome. We cannot rule out that some of these treatments may have been harmful to the patient.
This case illustrates the challenges in monitoring and treating patients with severe RCVS. Further studies have to be achieved to determine the role of TCD, especially at an early stage of the disease. In particular, continuous monitoring of CBFV should be evaluated in patients with RCVS. Despite the fatal outcome in our patients, we used several invasive therapies that may be effective in similar patients if initiated early enough.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Written informed consent was obtained from the individual's legal next of kin for the publication of any potentially identifiable images or data included in this article.
Author Contributions
GB and EC designed this article. GB drafted the first manuscript. AB, LF, ZK, DP, and EC contributed to interpretations of clinical and radiological details. All authors read and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
CBFcerebral blood flow
CBFVcerebral blood flow velocities
CSFcerebrospinal fluid
DSAdigital subtraction angiography
HLHhomonymous lateral hemianopsia
MAPmean arterial pressure
MCAmiddle cerebral artery
NCCTnon-contrast CT scanner
RCVSreversible cerebral vasoconstriction syndrome
SAHsubarachnoid hemorrhage
TCDtranscranial Doppler
THCtetrahydrocannabinol. | Fatal | ReactionOutcome | CC BY | 33658973 | 19,357,236 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Penile vein thrombosis'. | Partial segmental thrombosis of the corpus cavernosum associated with recreational use of sildenafil.
Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease involving thrombosis at the proximal corpus cavernosum. We describe the case of a 39-year-old African American man presenting with right groin pain who was diagnosed with PSTCC. Classic sonographic, computed tomography (CT), and magnetic resonance imaging (MRI) features were present. After conservative treatment with systemic anticoagulation, he had no long-term adverse effects or erectile dysfunction. Although various risk factors for PSTCC have been reported, this is the first documented case associated with recreational use of a phosphodiesterase inhibitor.
Introduction
Partial segmental thrombosis of the corpus cavernosum (PSTCC), also called partial priapism, is a rare condition with fewer than 60 cases reported over the last 40 years.1 Most information regarding imaging findings and treatment relies on case reports. There are several hypothesized risk factors but most cases are idiopathic. Patients have been managed with a variety of diagnostic and treatment modalities; however, the majority of cases can successfully be managed conservatively with good long-term outcomes. We present a case related to recreational use of sildenafil in a healthy 39-year-old African American man managed conservatively. We also demonstrate sonographic, CT, and MRI findings relating to this poorly understood entity in relation to our patient. To the best of our knowledge, this is the first reported case of PSTCC associated with recreational sildenafil use in our review of the literature.
Case description
A healthy, 39-year-old African American man presented to the Emergency Department with two days of right groin pain that radiated to the perineum. The patient denied history of trauma and reported having normal erections prior to the onset of symptoms. He admitted to intermittently using sildenafil off-label without a diagnosis of erectile dysfunction. The patient's medical history was otherwise unremarkable and he denied taking other medications. On physical examination, there was tenderness and rigidity to his proximal right corpus cavernosum at the base of his penis which extended into the perineum. The distal right corpus cavernosum, left corpus cavernosum, and glans penis were flaccid. The remainder of the examination was unremarkable. The patient was admitted for further evaluation and pain control.
The proximal right corpus cavernosum was aspirated and negative for abnormal cells and the corporal blood gas was consistent with ischemia. Sickle cell screen and peripheral blood smear were normal. He had an elevated D-dimer (0.72 mcg/mL) and C-reactive protein (10.4 mg/dL). His other laboratory results were unremarkable. Hematology was consulted for a hypercoagulability work-up. Initial contrast-enhanced CT of the pelvis demonstrated a marked edematous appearance of the proximal right corpus cavernosum with fascial enhancement (Fig. 1). A curvilinear focus of hyperattenuation was also noted and likely corresponded to a small region of tunica albuginea enhancement on the ventral right corpus cavernosum (Fig. 1). The left corpus cavernosum demonstrated minimal fascial enhancement without significant edema or enlargement. Penile ultrasound showed asymmetric fullness of the right corpus cavernosum and decreased blood flow (Fig. 2). The left corpus cavernosum was normal in sonographic appearance. MRI of the pelvis displayed a diffusely enlarged appearance of the proximal portion of the right corpus cavernosum with T2-weighted sequence signal hypointensity compared to the left (Fig. 3). The proximal left corpus cavernosum also demonstrated a mild degree of T2 hypointensity possibly secondary to restricted blood flow due to mass effect from right corpus cavernosum edema. The constellation of findings from these three imaging modalities and his physical examination were consistent with PSTCC of the right corpus cavernosum. Hematology recommended treatment with rivaroxaban 15mg twice daily for 21 days followed by 20mg once daily for a total of six months. Two weeks after discharge he reported resolution of pain and his examination showed significantly improved palpable fullness. He had normal erectile function and was no longer using sildenafil. At two months post-discharge, his examination had returned to baseline and at six months post-discharge, he did not have painful erections or erectile dysfunction.Fig. 1 Axial contrast enhanced CT images through the proximal corpora cavernosum. a The right corpus cavernosum demonstrates marked enlargement (black arrowhead). Fascial enhancement is also appreciated (white arrowhead). b Curvilinear enhancement is noted on more caudal slices likely corresponding to focal enhancement of the right corpus cavernosum and ventral tunica albuginea (arrow).
Fig. 1Fig. 2 Two ventral and cross sectional still sonographic images from the patient's penile sonographic exam. a Color doppler image shows decreased blood flow of an enlarged right corpus cavernosum. b The right corpus cavernosum is demonstrated to a better extent and demonstrates marked enlargement (arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2Fig. 3 T2 MRI sequences through the level of the corpora cavernosa. a Axial T2/STIR image demonstrated T2 hypointense signal within the proximal corpus cavernosum (arrow). A milder degree of T2 low signal is also appreciated within the proximal left corpus cavernosum (arrowhead). b An axial T2 sequence demonstrates T2 low signal within the right corpus cavernosum (arrowhead). No color is needed for Fig. 1 or Fig. 3. Color is needed for Fig. 2.
Fig. 3
Discussion
The pathophysiology of PSTCC is poorly understood. Cases that have been managed surgically report a septum of fibrous connective tissue located at the cruro-cavernosal junction, which may predispose patients to forming PSTCC at this location.2 While the majority of cases appear to be idiopathic, suggested risk factors include bike riding, perineal trauma, vigorous sexual activity, or hematological conditions. While priapism is a known potential complication associated with the use of sildenafil, the overall incidence is quite low. PSTCC has been reported in an older man with the use of prescribed sildenafil.2 To our knowledge, we present the first case of PSTCC associated with recreational use of sildenafil in a male with no documented diagnosis of erectile dysfunction.
The diagnosis of PSTCC can be made based on physical examination and with the aid of different imaging modalities. On physical examination, there is unilateral tender rigidity of the proximal corpus cavernosum in the setting of distal and contralateral flaccidity. Noninvasive imaging options include ultrasound, CT, and MRI. Ultrasound is readily available and noninvasive but technique can often be operator dependent. Findings can be confirmed with MRI as it can better delineate the segmental thrombosis and may demonstrate a thickened septum within the affected corpus cavernosum.3
Suggested treatment modalities have varied from conservative regimens to surgical intervention. Conservative medical treatment regimens include subcutaneous injections of low molecular weight heparin for at least six weeks with the addition of aspirin 325mg by mouth once daily or non-steroidal anti-inflammatory drugs.3,4 Rivaroxaban for up to six months combined with daily sildenafil, which can also be used to treat stuttering priapism, has also been reported.1 Alternatively, surgical intervention for refractory pain to evacuate the thrombus has been reported after aspiration/injection methods have failed.2 In conjunction with Hematology recommendations, we would recommend a six month course of rivaroxaban to prevent further thrombotic events. There is the added benefit of improved patient compliance and tolerability with oral medications. We also recommend close follow-up with Hematology to ensure a complete hypercoagulability evaluation. To date, there was no reported erectile dysfunction following resolution of the thrombus in our patient.
Conclusion
Partial segmental corpus cavernosum thromboses are typically the result of idiopathic or traumatic etiologies. Recreational use of sildenafil may place men at a higher risk of developing PSTCC and use should be documented in the initial evaluation. Diagnosis can be made with the combination of physical examination, sonography, CT, and MRI. PSTCC can be successfully treated conservatively with systemic anticoagulation with resolution of symptoms within three months.
Declaration of competing interest
Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. Government." | SILDENAFIL | DrugsGivenReaction | CC BY-NC-ND | 33659186 | 18,991,842 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Substance use'. | Partial segmental thrombosis of the corpus cavernosum associated with recreational use of sildenafil.
Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease involving thrombosis at the proximal corpus cavernosum. We describe the case of a 39-year-old African American man presenting with right groin pain who was diagnosed with PSTCC. Classic sonographic, computed tomography (CT), and magnetic resonance imaging (MRI) features were present. After conservative treatment with systemic anticoagulation, he had no long-term adverse effects or erectile dysfunction. Although various risk factors for PSTCC have been reported, this is the first documented case associated with recreational use of a phosphodiesterase inhibitor.
Introduction
Partial segmental thrombosis of the corpus cavernosum (PSTCC), also called partial priapism, is a rare condition with fewer than 60 cases reported over the last 40 years.1 Most information regarding imaging findings and treatment relies on case reports. There are several hypothesized risk factors but most cases are idiopathic. Patients have been managed with a variety of diagnostic and treatment modalities; however, the majority of cases can successfully be managed conservatively with good long-term outcomes. We present a case related to recreational use of sildenafil in a healthy 39-year-old African American man managed conservatively. We also demonstrate sonographic, CT, and MRI findings relating to this poorly understood entity in relation to our patient. To the best of our knowledge, this is the first reported case of PSTCC associated with recreational sildenafil use in our review of the literature.
Case description
A healthy, 39-year-old African American man presented to the Emergency Department with two days of right groin pain that radiated to the perineum. The patient denied history of trauma and reported having normal erections prior to the onset of symptoms. He admitted to intermittently using sildenafil off-label without a diagnosis of erectile dysfunction. The patient's medical history was otherwise unremarkable and he denied taking other medications. On physical examination, there was tenderness and rigidity to his proximal right corpus cavernosum at the base of his penis which extended into the perineum. The distal right corpus cavernosum, left corpus cavernosum, and glans penis were flaccid. The remainder of the examination was unremarkable. The patient was admitted for further evaluation and pain control.
The proximal right corpus cavernosum was aspirated and negative for abnormal cells and the corporal blood gas was consistent with ischemia. Sickle cell screen and peripheral blood smear were normal. He had an elevated D-dimer (0.72 mcg/mL) and C-reactive protein (10.4 mg/dL). His other laboratory results were unremarkable. Hematology was consulted for a hypercoagulability work-up. Initial contrast-enhanced CT of the pelvis demonstrated a marked edematous appearance of the proximal right corpus cavernosum with fascial enhancement (Fig. 1). A curvilinear focus of hyperattenuation was also noted and likely corresponded to a small region of tunica albuginea enhancement on the ventral right corpus cavernosum (Fig. 1). The left corpus cavernosum demonstrated minimal fascial enhancement without significant edema or enlargement. Penile ultrasound showed asymmetric fullness of the right corpus cavernosum and decreased blood flow (Fig. 2). The left corpus cavernosum was normal in sonographic appearance. MRI of the pelvis displayed a diffusely enlarged appearance of the proximal portion of the right corpus cavernosum with T2-weighted sequence signal hypointensity compared to the left (Fig. 3). The proximal left corpus cavernosum also demonstrated a mild degree of T2 hypointensity possibly secondary to restricted blood flow due to mass effect from right corpus cavernosum edema. The constellation of findings from these three imaging modalities and his physical examination were consistent with PSTCC of the right corpus cavernosum. Hematology recommended treatment with rivaroxaban 15mg twice daily for 21 days followed by 20mg once daily for a total of six months. Two weeks after discharge he reported resolution of pain and his examination showed significantly improved palpable fullness. He had normal erectile function and was no longer using sildenafil. At two months post-discharge, his examination had returned to baseline and at six months post-discharge, he did not have painful erections or erectile dysfunction.Fig. 1 Axial contrast enhanced CT images through the proximal corpora cavernosum. a The right corpus cavernosum demonstrates marked enlargement (black arrowhead). Fascial enhancement is also appreciated (white arrowhead). b Curvilinear enhancement is noted on more caudal slices likely corresponding to focal enhancement of the right corpus cavernosum and ventral tunica albuginea (arrow).
Fig. 1Fig. 2 Two ventral and cross sectional still sonographic images from the patient's penile sonographic exam. a Color doppler image shows decreased blood flow of an enlarged right corpus cavernosum. b The right corpus cavernosum is demonstrated to a better extent and demonstrates marked enlargement (arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2Fig. 3 T2 MRI sequences through the level of the corpora cavernosa. a Axial T2/STIR image demonstrated T2 hypointense signal within the proximal corpus cavernosum (arrow). A milder degree of T2 low signal is also appreciated within the proximal left corpus cavernosum (arrowhead). b An axial T2 sequence demonstrates T2 low signal within the right corpus cavernosum (arrowhead). No color is needed for Fig. 1 or Fig. 3. Color is needed for Fig. 2.
Fig. 3
Discussion
The pathophysiology of PSTCC is poorly understood. Cases that have been managed surgically report a septum of fibrous connective tissue located at the cruro-cavernosal junction, which may predispose patients to forming PSTCC at this location.2 While the majority of cases appear to be idiopathic, suggested risk factors include bike riding, perineal trauma, vigorous sexual activity, or hematological conditions. While priapism is a known potential complication associated with the use of sildenafil, the overall incidence is quite low. PSTCC has been reported in an older man with the use of prescribed sildenafil.2 To our knowledge, we present the first case of PSTCC associated with recreational use of sildenafil in a male with no documented diagnosis of erectile dysfunction.
The diagnosis of PSTCC can be made based on physical examination and with the aid of different imaging modalities. On physical examination, there is unilateral tender rigidity of the proximal corpus cavernosum in the setting of distal and contralateral flaccidity. Noninvasive imaging options include ultrasound, CT, and MRI. Ultrasound is readily available and noninvasive but technique can often be operator dependent. Findings can be confirmed with MRI as it can better delineate the segmental thrombosis and may demonstrate a thickened septum within the affected corpus cavernosum.3
Suggested treatment modalities have varied from conservative regimens to surgical intervention. Conservative medical treatment regimens include subcutaneous injections of low molecular weight heparin for at least six weeks with the addition of aspirin 325mg by mouth once daily or non-steroidal anti-inflammatory drugs.3,4 Rivaroxaban for up to six months combined with daily sildenafil, which can also be used to treat stuttering priapism, has also been reported.1 Alternatively, surgical intervention for refractory pain to evacuate the thrombus has been reported after aspiration/injection methods have failed.2 In conjunction with Hematology recommendations, we would recommend a six month course of rivaroxaban to prevent further thrombotic events. There is the added benefit of improved patient compliance and tolerability with oral medications. We also recommend close follow-up with Hematology to ensure a complete hypercoagulability evaluation. To date, there was no reported erectile dysfunction following resolution of the thrombus in our patient.
Conclusion
Partial segmental corpus cavernosum thromboses are typically the result of idiopathic or traumatic etiologies. Recreational use of sildenafil may place men at a higher risk of developing PSTCC and use should be documented in the initial evaluation. Diagnosis can be made with the combination of physical examination, sonography, CT, and MRI. PSTCC can be successfully treated conservatively with systemic anticoagulation with resolution of symptoms within three months.
Declaration of competing interest
Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. Government." | SILDENAFIL | DrugsGivenReaction | CC BY-NC-ND | 33659186 | 18,991,842 | 2021-05 |
What was the outcome of reaction 'Penile vein thrombosis'? | Partial segmental thrombosis of the corpus cavernosum associated with recreational use of sildenafil.
Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease involving thrombosis at the proximal corpus cavernosum. We describe the case of a 39-year-old African American man presenting with right groin pain who was diagnosed with PSTCC. Classic sonographic, computed tomography (CT), and magnetic resonance imaging (MRI) features were present. After conservative treatment with systemic anticoagulation, he had no long-term adverse effects or erectile dysfunction. Although various risk factors for PSTCC have been reported, this is the first documented case associated with recreational use of a phosphodiesterase inhibitor.
Introduction
Partial segmental thrombosis of the corpus cavernosum (PSTCC), also called partial priapism, is a rare condition with fewer than 60 cases reported over the last 40 years.1 Most information regarding imaging findings and treatment relies on case reports. There are several hypothesized risk factors but most cases are idiopathic. Patients have been managed with a variety of diagnostic and treatment modalities; however, the majority of cases can successfully be managed conservatively with good long-term outcomes. We present a case related to recreational use of sildenafil in a healthy 39-year-old African American man managed conservatively. We also demonstrate sonographic, CT, and MRI findings relating to this poorly understood entity in relation to our patient. To the best of our knowledge, this is the first reported case of PSTCC associated with recreational sildenafil use in our review of the literature.
Case description
A healthy, 39-year-old African American man presented to the Emergency Department with two days of right groin pain that radiated to the perineum. The patient denied history of trauma and reported having normal erections prior to the onset of symptoms. He admitted to intermittently using sildenafil off-label without a diagnosis of erectile dysfunction. The patient's medical history was otherwise unremarkable and he denied taking other medications. On physical examination, there was tenderness and rigidity to his proximal right corpus cavernosum at the base of his penis which extended into the perineum. The distal right corpus cavernosum, left corpus cavernosum, and glans penis were flaccid. The remainder of the examination was unremarkable. The patient was admitted for further evaluation and pain control.
The proximal right corpus cavernosum was aspirated and negative for abnormal cells and the corporal blood gas was consistent with ischemia. Sickle cell screen and peripheral blood smear were normal. He had an elevated D-dimer (0.72 mcg/mL) and C-reactive protein (10.4 mg/dL). His other laboratory results were unremarkable. Hematology was consulted for a hypercoagulability work-up. Initial contrast-enhanced CT of the pelvis demonstrated a marked edematous appearance of the proximal right corpus cavernosum with fascial enhancement (Fig. 1). A curvilinear focus of hyperattenuation was also noted and likely corresponded to a small region of tunica albuginea enhancement on the ventral right corpus cavernosum (Fig. 1). The left corpus cavernosum demonstrated minimal fascial enhancement without significant edema or enlargement. Penile ultrasound showed asymmetric fullness of the right corpus cavernosum and decreased blood flow (Fig. 2). The left corpus cavernosum was normal in sonographic appearance. MRI of the pelvis displayed a diffusely enlarged appearance of the proximal portion of the right corpus cavernosum with T2-weighted sequence signal hypointensity compared to the left (Fig. 3). The proximal left corpus cavernosum also demonstrated a mild degree of T2 hypointensity possibly secondary to restricted blood flow due to mass effect from right corpus cavernosum edema. The constellation of findings from these three imaging modalities and his physical examination were consistent with PSTCC of the right corpus cavernosum. Hematology recommended treatment with rivaroxaban 15mg twice daily for 21 days followed by 20mg once daily for a total of six months. Two weeks after discharge he reported resolution of pain and his examination showed significantly improved palpable fullness. He had normal erectile function and was no longer using sildenafil. At two months post-discharge, his examination had returned to baseline and at six months post-discharge, he did not have painful erections or erectile dysfunction.Fig. 1 Axial contrast enhanced CT images through the proximal corpora cavernosum. a The right corpus cavernosum demonstrates marked enlargement (black arrowhead). Fascial enhancement is also appreciated (white arrowhead). b Curvilinear enhancement is noted on more caudal slices likely corresponding to focal enhancement of the right corpus cavernosum and ventral tunica albuginea (arrow).
Fig. 1Fig. 2 Two ventral and cross sectional still sonographic images from the patient's penile sonographic exam. a Color doppler image shows decreased blood flow of an enlarged right corpus cavernosum. b The right corpus cavernosum is demonstrated to a better extent and demonstrates marked enlargement (arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2Fig. 3 T2 MRI sequences through the level of the corpora cavernosa. a Axial T2/STIR image demonstrated T2 hypointense signal within the proximal corpus cavernosum (arrow). A milder degree of T2 low signal is also appreciated within the proximal left corpus cavernosum (arrowhead). b An axial T2 sequence demonstrates T2 low signal within the right corpus cavernosum (arrowhead). No color is needed for Fig. 1 or Fig. 3. Color is needed for Fig. 2.
Fig. 3
Discussion
The pathophysiology of PSTCC is poorly understood. Cases that have been managed surgically report a septum of fibrous connective tissue located at the cruro-cavernosal junction, which may predispose patients to forming PSTCC at this location.2 While the majority of cases appear to be idiopathic, suggested risk factors include bike riding, perineal trauma, vigorous sexual activity, or hematological conditions. While priapism is a known potential complication associated with the use of sildenafil, the overall incidence is quite low. PSTCC has been reported in an older man with the use of prescribed sildenafil.2 To our knowledge, we present the first case of PSTCC associated with recreational use of sildenafil in a male with no documented diagnosis of erectile dysfunction.
The diagnosis of PSTCC can be made based on physical examination and with the aid of different imaging modalities. On physical examination, there is unilateral tender rigidity of the proximal corpus cavernosum in the setting of distal and contralateral flaccidity. Noninvasive imaging options include ultrasound, CT, and MRI. Ultrasound is readily available and noninvasive but technique can often be operator dependent. Findings can be confirmed with MRI as it can better delineate the segmental thrombosis and may demonstrate a thickened septum within the affected corpus cavernosum.3
Suggested treatment modalities have varied from conservative regimens to surgical intervention. Conservative medical treatment regimens include subcutaneous injections of low molecular weight heparin for at least six weeks with the addition of aspirin 325mg by mouth once daily or non-steroidal anti-inflammatory drugs.3,4 Rivaroxaban for up to six months combined with daily sildenafil, which can also be used to treat stuttering priapism, has also been reported.1 Alternatively, surgical intervention for refractory pain to evacuate the thrombus has been reported after aspiration/injection methods have failed.2 In conjunction with Hematology recommendations, we would recommend a six month course of rivaroxaban to prevent further thrombotic events. There is the added benefit of improved patient compliance and tolerability with oral medications. We also recommend close follow-up with Hematology to ensure a complete hypercoagulability evaluation. To date, there was no reported erectile dysfunction following resolution of the thrombus in our patient.
Conclusion
Partial segmental corpus cavernosum thromboses are typically the result of idiopathic or traumatic etiologies. Recreational use of sildenafil may place men at a higher risk of developing PSTCC and use should be documented in the initial evaluation. Diagnosis can be made with the combination of physical examination, sonography, CT, and MRI. PSTCC can be successfully treated conservatively with systemic anticoagulation with resolution of symptoms within three months.
Declaration of competing interest
Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. Government." | Recovered | ReactionOutcome | CC BY-NC-ND | 33659186 | 18,991,842 | 2021-05 |
What was the outcome of reaction 'Substance use'? | Partial segmental thrombosis of the corpus cavernosum associated with recreational use of sildenafil.
Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease involving thrombosis at the proximal corpus cavernosum. We describe the case of a 39-year-old African American man presenting with right groin pain who was diagnosed with PSTCC. Classic sonographic, computed tomography (CT), and magnetic resonance imaging (MRI) features were present. After conservative treatment with systemic anticoagulation, he had no long-term adverse effects or erectile dysfunction. Although various risk factors for PSTCC have been reported, this is the first documented case associated with recreational use of a phosphodiesterase inhibitor.
Introduction
Partial segmental thrombosis of the corpus cavernosum (PSTCC), also called partial priapism, is a rare condition with fewer than 60 cases reported over the last 40 years.1 Most information regarding imaging findings and treatment relies on case reports. There are several hypothesized risk factors but most cases are idiopathic. Patients have been managed with a variety of diagnostic and treatment modalities; however, the majority of cases can successfully be managed conservatively with good long-term outcomes. We present a case related to recreational use of sildenafil in a healthy 39-year-old African American man managed conservatively. We also demonstrate sonographic, CT, and MRI findings relating to this poorly understood entity in relation to our patient. To the best of our knowledge, this is the first reported case of PSTCC associated with recreational sildenafil use in our review of the literature.
Case description
A healthy, 39-year-old African American man presented to the Emergency Department with two days of right groin pain that radiated to the perineum. The patient denied history of trauma and reported having normal erections prior to the onset of symptoms. He admitted to intermittently using sildenafil off-label without a diagnosis of erectile dysfunction. The patient's medical history was otherwise unremarkable and he denied taking other medications. On physical examination, there was tenderness and rigidity to his proximal right corpus cavernosum at the base of his penis which extended into the perineum. The distal right corpus cavernosum, left corpus cavernosum, and glans penis were flaccid. The remainder of the examination was unremarkable. The patient was admitted for further evaluation and pain control.
The proximal right corpus cavernosum was aspirated and negative for abnormal cells and the corporal blood gas was consistent with ischemia. Sickle cell screen and peripheral blood smear were normal. He had an elevated D-dimer (0.72 mcg/mL) and C-reactive protein (10.4 mg/dL). His other laboratory results were unremarkable. Hematology was consulted for a hypercoagulability work-up. Initial contrast-enhanced CT of the pelvis demonstrated a marked edematous appearance of the proximal right corpus cavernosum with fascial enhancement (Fig. 1). A curvilinear focus of hyperattenuation was also noted and likely corresponded to a small region of tunica albuginea enhancement on the ventral right corpus cavernosum (Fig. 1). The left corpus cavernosum demonstrated minimal fascial enhancement without significant edema or enlargement. Penile ultrasound showed asymmetric fullness of the right corpus cavernosum and decreased blood flow (Fig. 2). The left corpus cavernosum was normal in sonographic appearance. MRI of the pelvis displayed a diffusely enlarged appearance of the proximal portion of the right corpus cavernosum with T2-weighted sequence signal hypointensity compared to the left (Fig. 3). The proximal left corpus cavernosum also demonstrated a mild degree of T2 hypointensity possibly secondary to restricted blood flow due to mass effect from right corpus cavernosum edema. The constellation of findings from these three imaging modalities and his physical examination were consistent with PSTCC of the right corpus cavernosum. Hematology recommended treatment with rivaroxaban 15mg twice daily for 21 days followed by 20mg once daily for a total of six months. Two weeks after discharge he reported resolution of pain and his examination showed significantly improved palpable fullness. He had normal erectile function and was no longer using sildenafil. At two months post-discharge, his examination had returned to baseline and at six months post-discharge, he did not have painful erections or erectile dysfunction.Fig. 1 Axial contrast enhanced CT images through the proximal corpora cavernosum. a The right corpus cavernosum demonstrates marked enlargement (black arrowhead). Fascial enhancement is also appreciated (white arrowhead). b Curvilinear enhancement is noted on more caudal slices likely corresponding to focal enhancement of the right corpus cavernosum and ventral tunica albuginea (arrow).
Fig. 1Fig. 2 Two ventral and cross sectional still sonographic images from the patient's penile sonographic exam. a Color doppler image shows decreased blood flow of an enlarged right corpus cavernosum. b The right corpus cavernosum is demonstrated to a better extent and demonstrates marked enlargement (arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2Fig. 3 T2 MRI sequences through the level of the corpora cavernosa. a Axial T2/STIR image demonstrated T2 hypointense signal within the proximal corpus cavernosum (arrow). A milder degree of T2 low signal is also appreciated within the proximal left corpus cavernosum (arrowhead). b An axial T2 sequence demonstrates T2 low signal within the right corpus cavernosum (arrowhead). No color is needed for Fig. 1 or Fig. 3. Color is needed for Fig. 2.
Fig. 3
Discussion
The pathophysiology of PSTCC is poorly understood. Cases that have been managed surgically report a septum of fibrous connective tissue located at the cruro-cavernosal junction, which may predispose patients to forming PSTCC at this location.2 While the majority of cases appear to be idiopathic, suggested risk factors include bike riding, perineal trauma, vigorous sexual activity, or hematological conditions. While priapism is a known potential complication associated with the use of sildenafil, the overall incidence is quite low. PSTCC has been reported in an older man with the use of prescribed sildenafil.2 To our knowledge, we present the first case of PSTCC associated with recreational use of sildenafil in a male with no documented diagnosis of erectile dysfunction.
The diagnosis of PSTCC can be made based on physical examination and with the aid of different imaging modalities. On physical examination, there is unilateral tender rigidity of the proximal corpus cavernosum in the setting of distal and contralateral flaccidity. Noninvasive imaging options include ultrasound, CT, and MRI. Ultrasound is readily available and noninvasive but technique can often be operator dependent. Findings can be confirmed with MRI as it can better delineate the segmental thrombosis and may demonstrate a thickened septum within the affected corpus cavernosum.3
Suggested treatment modalities have varied from conservative regimens to surgical intervention. Conservative medical treatment regimens include subcutaneous injections of low molecular weight heparin for at least six weeks with the addition of aspirin 325mg by mouth once daily or non-steroidal anti-inflammatory drugs.3,4 Rivaroxaban for up to six months combined with daily sildenafil, which can also be used to treat stuttering priapism, has also been reported.1 Alternatively, surgical intervention for refractory pain to evacuate the thrombus has been reported after aspiration/injection methods have failed.2 In conjunction with Hematology recommendations, we would recommend a six month course of rivaroxaban to prevent further thrombotic events. There is the added benefit of improved patient compliance and tolerability with oral medications. We also recommend close follow-up with Hematology to ensure a complete hypercoagulability evaluation. To date, there was no reported erectile dysfunction following resolution of the thrombus in our patient.
Conclusion
Partial segmental corpus cavernosum thromboses are typically the result of idiopathic or traumatic etiologies. Recreational use of sildenafil may place men at a higher risk of developing PSTCC and use should be documented in the initial evaluation. Diagnosis can be made with the combination of physical examination, sonography, CT, and MRI. PSTCC can be successfully treated conservatively with systemic anticoagulation with resolution of symptoms within three months.
Declaration of competing interest
Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. Government." | Recovered | ReactionOutcome | CC BY-NC-ND | 33659186 | 18,991,842 | 2021-05 |
What was the outcome of reaction 'Immune-mediated encephalopathy'? | Recognizing encephalopathy in immune checkpoint inhibitor therapy: A single-center experience.
In this pilot study, we examined the characteristics of patients with and without central nervous system (CNS) malignancies who developed immune checkpoint inhibitor (ICI)-induced encephalopathy.
We identified adult patients treated with ICIs between 1 January 2013 and 9 May 2018 at our tertiary care center who developed encephalopathy within 30 days of the last dose of ICI without other explained causes. Demographic and clinical features were compared between patients with primary and metastatic malignant CNS tumors and those without.
Of the 480 patients treated with ICIs, 14 (2.9%) developed encephalopathy induced by nivolumab (8), pembrolizumab (4), and combined ipilimumab-nivolumab (2). Median age was 64.5 years. Patients with CNS malignancies tolerated more treatment cycles and developed encephalopathy later than patients without CNS lesions (20 and 32 days, respectively, p = 0.04) following ICI initiation. Four of seven patients with CNS tumors developed new contrast-enhancing lesions on brain imaging despite having no changes on imaging for a median of 61 (30-545) days. Electroencephalogram (EEG) revealed features of generalized dysfunction in patients in both cohorts. Two patients without and three with CNS malignancies were treated with steroids. Two thirds of patients without and 29% of those with CNS malignancies expired during ICI therapy or shortly thereafter.
Lack of the uniform evaluation limits the definitive conclusion of the cause of encephalopathy in some patients but reflects the standard of care at the time of their assessment. ICI-associated neurotoxicity presenting with encephalopathy is an ominous complication of ICI therapy, especially if left untreated. Prompt recognition and involvement of multidisciplinary care, including neurologists, would facilitate timely administration of recommended therapies.
Lay summary
Patients receiving treatment with immune checkpoint inhibitors, a novel class of anticancer medications, can develop confusion, decreased responsiveness, headaches, and seizures that, if left untreated, can be fatal. We assessed the frequency of these neurological side effects in patients with and without tumors of the brain and compared their management at our institution. We found that the evaluation of patients in both groups was often incomplete. We also determined that the majority of patients were not treated according to the recommended guidelines and most of these patients were deceased shortly following their admission to the hospital. We concluded that the complication of immune checkpoint inhibitor therapy is not readily recognized by practitioners. We summarized the existing recommendations for the evaluation and treatment of these patients and proposed that neurologists be included in multidisciplinary efforts to treat these patients.
1 INTRODUCTION
Immune checkpoint inhibitors (ICIs), a novel class of antitumor monoclonal antibodies, have revolutionized treatment of relapsing advanced tumors of the skin, solid organs, and lymphatic system. 1 These highly effective therapies interfere with the inhibitory effects of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and programmed cell death/programmed death ligand‐1 (PD1/PDL1) proteins in T‐cell regulatory pathways, resulting in markedly stronger activity of T cells against tumor cells. 1
The immune activation may lead to ICI‐related neurological adverse effects (irAE‐N), manifested as weakness, fever, headache, altered mental status, abnormal movements, or seizures. 2 , 3 High‐grade central nervous system (CNS) toxicities were reported in fewer than 1% of patients treated with ICIs and developed with a median latency of 6 weeks. 4 , 5 The phenomena of pseudoprogression (increase in size due to therapy) and hyperprogression (doubling in size) of brain tumors following ICI therapy have also been reported. 6 , 7 However, only one patient was reported to present with encephalopathy. 8
Evaluation of patients with suspected ICI‐related neurotoxicity includes cerebrospinal fluid (CSF) analysis, brain imaging, and EEG to assess for the presence of central inflammation, neuronal autoantibodies, and non‐convulsive seizures. 2 If irAE‐N is confirmed, treatment involves discontinuing ICI and initiation of immunotherapy with steroids, intravenous immunoglobulins (IVIG), plasma exchange, rituximab, or natalizumab. 5 However, the clinical management of encephalopathy in patients with primary or metastatic brain malignancies may require a different approach from that in patients without brain lesions. Specifically, the lumbar puncture recommended for the evaluation of encephalopathy related to the ICI therapy is contraindicated in most patients with space‐occupying CNS lesions due to the risk of herniation and thus it may not be performed. 9 This is particularly applicable to patients who present with an altered mental status when the existence of an increased intracranial pressure cannot be reasonably ruled out. Therefore, the diagnosis of irAE‐N in these patients may need to be established without the CSF examination. Furthermore, some patients with CNS malignancies who are already receiving the corticosteroids to reduce cerebral edema may be managed differently than those without steroid use. The existing guidelines for the management of the irAE‐N related to the ICI therapy do not provide the distinctions specific to patients with CNS malignancies and the existing literature is limited. 10 , 11 Therefore, a consensus on specific approaches to the diagnosis and management of patients with and without brain malignancies is urgently needed.
Early diagnosis of irAE‐N in patients receiving ICIs may improve the prognosis. 3 In this single‐center retrospective pilot study, we assessed the clinical course, management approaches, and outcomes of patients with ICI‐induced encephalopathy, with a focus on comparisons between groups with and without CNS malignancies.
2 METHODS
2.1 Study population
Retrospective chart review and analysis were conducted with the approval of the Institutional Review Board at the University of Nebraska Medical Center. Using a custom SQL query, we identified patients who were treated with ICIs from 1 January 2013 to 9 May 2018 and developed encephalopathy. The following key words were applied: “nivolumab”, “pembrolizumab”, “ipilimumab”, “atezolizumab”, “durvalumab,”, “avelumab”, “encephalopathy”, “confusion”, “altered mental status”, and “delirium”. Following the identification of these patients from the electronic medical record query, the clinical documentation was reviewed to extract the clinical, laboratory, radiological, and EEG data. A comprehensive metabolic panel, including liver function tests and complete blood count as well as brain images, needed to be documented for the patients to be included. Additional tests (i.e., blood cultures, CSF examination, and EEG) were performed at the discretion of the treating team.
2.2 Case identification
ICI‐induced encephalopathy was defined as a change from baseline cognitive status within 30 days of the last dose of ICI without other identified causes of encephalopathy. The inclusion criteria were as follows: being treated with the first or repeated cycles of ICIs for the systemic or CNS malignancy, being within 30 days from the last dose of the ICI, and being diagnosed with altered mental status, encephalopathy, or delirium upon presentation to the hospital. Patients with sepsis, clinically significant abnormalities in the sodium or calcium metabolism at the discretion of the treating team, acute kidney, respiratory, and hepatic failure, or those with underlying dementia were excluded.
Two neurologists with expertise in general and autoimmune epilepsy (P.D. and O.T.) reviewed all cases to ascertain final diagnoses. The severity of encephalopathy was established according to the classification outlined in the Common Terminology Criteria for Adverse Events (CTCAE), Version 5. 12 We abstracted and compared demographic and clinical characteristics of patients with and without primary or metastatic CNS malignancies. Mann‐Whitney U tests and Fisher's exact tests were applied to compare continuous and categorical variables, respectively (GraphPad Software, Inc., San Diego, CA).
3 RESULTS
There were 480 adult patients who were treated with at least one ICI, such as atezolizumab (33), avelumab (4), durvalumab (20), ipilimumab (65), nivolumab (209), and pembrolizumab (149). Thirty‐two patients developed encephalopathy. Eighteen patients who developed encephalopathy due to other etiologies (e.g., abnormalities of sodium and calcium metabolism, urinary tract infection, pneumonia, sepsis, etc) were excluded (Figure 1). Of the remaining 14 cases, seven had primary (2) or metastatic tumors (5), and the other seven were without any malignant CNS tumors. Ten patients (2%) developed mild encephalopathy while four patients (0.8%) had severe encephalopathy. Lack of the EEG and CSF examination data precludes the definitive conclusion on the etiology of encephalopathy in some patients.
FIGURE 1 Flow chart of patient selection for the case series. ICI, immune checkpoint inhibitor
The patients without CNS malignancies had a median age of 63 (45–82) years, and 43% were male (Table 1, Supplemental Table S1). The median number of cycles of ICI therapy was one (1–3). The most common presenting neurologic features were acute confusion and generalized weakness, which developed with a median latency of 20 (3–50) days from the first ICI treatment (Tables 1 and 2). There were five and two patients with grades 2 and 3 encephalopathy, respectively. CSF was obtained in one patient. The fluid was unremarkable, although autoimmune antibody studies were not ordered. EEGs were obtained in four patients and demonstrated generalized slowing, background disorganization, and generalized periodic discharges (GPDs) with triphasic morphology (Table 2). Two patients received steroids and one had resolution of encephalopathy. Two other patients received supportive care and had transient improvement of mental status. The ICIs were held in five patients, while the treatment plan was not specified for two other patients who did not survive until their next treatment cycle. One patient died within 3 days of admission, and four died later by other causes (Table 2).
TABLE 1 Demographic and clinical characteristics of patients with ICI‐induced encephalopathy
Without brain tumor (n = 7) With brain tumor (n = 7) p‐value
Chemotherapy regimen (number of patients) N (2), P (3), I + N (2) N (6), P (1)
Median age, years (range) 63 (45–82) 65 (49–73) 0.97 a
Sex (%) F (57%), M (43%) F (14%), M (86%) 0.27 b
Median number of chemotherapy cycles prior to encephalopathy (range) 1 (1–3) 3 (1–10) 0.04 a
Median latency to encephalopathy from first ICI cycle, days (range) 20 (3–50) 32 (9–133) 0.04 a
Neurology consulted, % total 57% 57% <0.99 b
Treated with steroids, % total 29% 43% <0.99 b
Mortality at discharge, % total 14% 29% <0.99 b
Mortality by 30 days post‐discharge, % total 67% c 29% 0.29 b
Abbreviations: F, female; I, ipilimumab; M, male; N, nivolumab; P, pembrolizumab.
a Mann‐Whitney U test;
b Fisher's exact test;
c One value missing, unaccounted for in calculation.
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TABLE 2 Clinical course and outcomes of patients with ICI‐induced encephalopathy
ID Age (years) and sex ICI, latency (days) # of ICI cycles Cancer type EEG findings AMS Grade Initial brain imaging for AMS Management Outcomes
Patients without brain lesions
1 82 F I, N, 50 3 Metastatic neuroendocrine tumor None 2 CT: Unremarkable No steroids. Patient expired before next ICI dose Expired in 3 days from onset of encephalopathy
2 78 M P, 20 1 Metastatic neuroendocrine tumor None 2 CT: Mild atrophy, white matter disease No steroids. Patient discharged to comfort measures before next ICI. Discharged on comfort measures, expired ≤30 days post‐discharge
3 81 F N, 6 1 Non‐small cell lung cancer None 2 MRI: Moderate volume loss, small vessel disease, small lacunar infarcts No steroids, held ICI Improved, ICI restarted, developed recurrent encephalopathy, discharged on comfort measures, expired ≤30 days post‐discharge
4 a 45 M I, N, 3 2 Neuroendocrine tumor Background slowing and disorganization 2 MRI: Subependymoma, unchanged Neurologist involved. Started oral prednisone, discontinued ICI Mental status improved remarkably. Expired >30 days post‐discharge from other complications
5 48 F N, 25 1 Non‐small cell lung cancer Generalized slowing 3 MRI: Punctate subcortical foci, likely microangiopathy Neurologist involved. No steroids, discontinued ICI Discharged on comfort measures, expired ≤30 days post‐discharge
6 63 F P, 27 2 Diffuse large B‐cell lymphoma Generalized slowing, GPDs with triphasic morphology 2 MRI: Unremarkable Neurologist involved. Started IV methylprednisolone, discontinued ICI Discharged on comfort measures, expired >30 days post‐discharge
7 58 M P, 6 1 Non‐small cell lung cancer Moderate diffuse slowing 3 MRI: Diffuse cerebral volume loss, mild ventriculomegaly Neurologist involved. No steroids, discontinued ICI Improved, discharged home. Readmitted for AMS and discharged to hospice. Date of death unknown
Patients with brain lesions
1 68 M N, 113 6 Small cell and non‐small carcinoma of lung, brain metastasis None 2 MRI: Left frontal lobe mass and 4 ring‐enhancing lesions in the left hemisphere; new from previous MRI Continued previous oral dexamethasone, discontinued ICI Improved
2 73 M N, 32 7 Non‐small cell carcinoma of lung, brain and bone metastases None 2 MRI: Multifocal small enhancing brain nodules consistent with metastatic disease No steroids, ICI was held Improved, ICI was restarted
3 61 M N, 133 10 Non‐small cell carcinoma of lung, brain and spinal metastases None 2 MRI: Multifocal metastatic disease to the brain, leptomeningeal metastatic disease to the brain No steroids, ICI was held Improved, ICI was restarted
4 61 M N, 26 2 Anaplastic astrocytoma None 2 MRI: Increased size of mass in right frontotemporal lobes and basal ganglia, suspicious for progression of tumor; evolution of prior right MCA infarcts Neurologist involved, Started IV dexamethasone, resumed ICI Discharged to home, presented to office for follow‐up then referred for comfort care. Expired >30 days post‐discharge.
5 49 M P, 9 1 Esophageal cancer, brain metastases Mild diffuse slowing 2 CT: Irregular area of increased attenuation in the interhemispheric fissure corresponding to probable meningeal metastases on previous MRI Neurologist involved. No steroids. Patient expired before next ICI dose. Deceased in 7 days from onset of encephalopathy
6 65 M N, 29 3 Non‐small cell carcinoma of lung, brain metastases Generalized slowing, focal slowing in right centroparietal region 3 MRI: New definitive contrast‐enhancing lesion and questionable lesion suspicious for metastatic disease Neurologist involved. No steroids. Patient expired before next ICI dose Deceased in 9 days from onset of encephalopathy
7 b 69 F N, 54 4 Glioblastoma multiforme Severe diffuse slowing, frequent GPDs with triphasic morphology and sharp‐and‐slow wave discharges 3 MRI: Expansible FLAIR hyperintensity surrounding atrium of right lateral ventricle with minimal enhancement concerning for progressive disease Neurologist involved. Started IV dexamethasone, discontinued ICI Improved
Abbreviations: AMS, altered mental status; CSF, cerebrospinal fluid; CT, computerized tomography; EEG, electroencephalogram; F, female; FLAIR, fluid attenuation inversion recovery; I, ipilimumab; ICI, immune checkpoint inhibitor; IV, intravenous; M, male; MRI, magnetic resonance imaging; N, nivolumab; P, pembrolizumab; WBC, white blood cell count.
a CSF analysis: glucose 77 mg/dL, protein 36 mg/dL, WBC 1/cm2;
b CSF analysis: glucose 139 mg/dL, protein 55 mg/dL, WBC 10/cm2, neutrophils 53%.
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In the cohort with primary or metastatic brain tumors and meningeal carcinomatosis, the median age (p = 0.97) and gender distribution (p = 0.27) were similar to those without CNS malignancies (Table 1, Supplemental Table S2). Five of seven patients received the ICIs for the progression of their primary systemic tumors and none of them had encephalopathy at the start of treatment. There were five and two patients with grades 2 and 3 encephalopathy, respectively, at the time of their admission. Patients with brain tumors tolerated more treatment cycles and developed encephalopathy 12 days later than patients without CNS tumors (p = 0.04). EEG was obtained in three patients and revealed mild to severe generalized slowing, interictal epileptiform discharges, and GPDs with triphasic morphology (Table 2). Four (57%) patients demonstrated new or evolved brain lesions on MRI compared to imaging obtained in a median of 61 (30–545) days prior to onset of encephalopathy. All three patients who received immunotherapy and two who were managed supportively improved, while two others were deceased within 9 days of developing encephalopathy (Table 2). The ICIs were stopped in four patients and continued in one patient, while two other patients have expired before their next scheduled cycle (Table 2). The overall mortality at discharge (p < 0.99) and 30 days post‐discharge (p = 0.29) were similar in both groups (Table 1). The increase in the lesion number or size compared to the most recent previous brain imaging scans obtained at different time intervals was noted in patients 1, 4, 6, and 7 (Table 2, Supplemental Data). Therefore, the diagnosis of ICI‐associated encephalopathy in these patients was established with less certainty than in patients who had no changes on the brain imaging.
Neurologists were involved in the care of four (57%) patients in each group. Specifically, of 14 patients, three were treated in 2015, four in 2016, four in 2017, and three in 2018 (Supplemental Tables S1 and S2). The neurology team was not involved in the management of patients treated in 2015. None of these patients underwent EEG and CSF examinations or received steroids. In 2016, three of four patients were co‐managed by a neurologist who recommended EEG and CSF examinations in all patients and steroid therapy in two patients. In 2017, the neurology team was similarly involved in the management of three of four patients with ICI‐induced encephalopathy. In that year, all three patients managed by a neurologist underwent EEG, two had the CSF examination and one was treated with steroids. In 2018, one of three patients was managed by a neurologist and underwent EEG but did not receive steroids.
4 DISCUSSION
In this retrospective case series, we summarized and compared the clinical courses and outcomes of encephalopathy associated with the ICI therapy in cancer patients with and without malignant brain lesions. The temporal course of encephalopathy in relation to the start of the ICI therapy, along with a retrospective analysis of available diagnostic features and exclusion of other potential etiologies of altered mental status supported the relationship between the ICI and the onset of encephalopathy (Supplemental Tables S1 and S2). We found that 2% and 0.8% of patients treated with ICIs at our center developed mild and severe encephalopathy, respectively, that could not be attributed to other etiologies. This incidence is comparable to that previously reported rates in studies where patients with primary and metastatic brain cancers were excluded. 3 , 5
Neurologists were consulted in fewer than 60% of the cases and only five (36%) patients in our case series received conventional treatment for ICI‐related encephalopathy. Among the five patients treated with steroids, four were co‐managed by neurologists. It is likely that, in the remaining patients, the treating physicians at the time were not familiar with the phenomena of irAE‐N. However, our study was not large enough to determine if the inclusion of a clinician with neurology expertise or the assessment being performed more recently would improve the success of managing these patients. Further studies designed to assess the benefits of multidisciplinary approach in treating the irAE‐N will aid in refining the management guidelines for these patients. One patient in our study with a lung carcinoma metastatic to the brain was already receiving a steroid therapy at the time of manifestation of encephalopathy. Depending on the timing of steroid administration, the former may restrict tumor‐specific immune response to checkpoint inhibition by impairing T‐lymphocyte activation 13 ; these adaptations may potentially influence the risk of developing the neurological toxicity during the therapy with ICIs. While it was shown that concurrent use of steroids was associated with the decreased overall response rate and survival in patients receiving ICIs for lung cancer, it is not clear whether the risk of neurotoxicity was similarly affected in these patients. 14
While headaches, encephalopathy, and immune‐mediated meningitis in previous studies developed in a median latency of 6 weeks, the latency to ICI‐related encephalopathy in our study was much shorter. 4 Interestingly, patients without malignant CNS disease developed cognitive deterioration much earlier than those with stable brain tumors. Possible explanations can be that the patients without brain lesions had more advanced stages of primary malignancies. Future prospective studies would allow to determine whether the location, histologic type, and stage of tumor contribute to the development of iatrogenic encephalopathy in patients receiving ICIs.
Mortality in both groups was high, with 29% and 67% of patients with and without brain tumors expiring by 30 days after discharge. These rates were higher than the reported 19% mortality among 200 cases of ICI‐induced encephalitis. 2 However, in our study, ancillary tests were largely limited to brain imaging, and it is unclear whether the encephalopathy in patients who did not receive lumbar puncture or EEG was compounded by the presence of meningoencephalitis or non‐convulsive seizures.
Fifty‐seven percent of patients with CNS lesions and encephalopathy had an increase in lesion number or tumor size, which were stable in previous brain imaging. Although we did not apply formal radiological criteria to establish pseudo‐ or hyperprogression of the CNS tumors, we recognize that they may be potential contributors to encephalopathy. Reports on encephalopathy and pseudo‐ or hyperprogression of metastatic CNS tumors in the setting of ICI therapy remain limited. 8 , 15 The tumor enlargement could potentially represent an enhanced inflammatory response from the direct invasion of the immune effector cells at the CNS tumor site contributing to tumor necrosis and edema. 16 Indeed, encephalopathy and focal interictal activity associated with pseudoprogression of metastatic CNS melanoma in response to ipilimumab were histologically confirmed to be accompanied by immune‐mediated inflammation and edema with extensive tumor necrosis. 16 In some patients, such a response was accompanied by prolonged stabilization of the CNS tumor. This brings an intriguing possibility that an initial increase in tumor size may correlate with the high success of ICI therapy in malignant CNS disease. 16 Patients with enlarging CNS tumors in our study were able to tolerate longer therapies before manifesting encephalopathy. This may reflect the limited CNS accessibility of ICIs and longer times required to mount an inflammatory response to the brain compared to tissues outside of the brain–blood barrier. Our study, however, was limited by its retrospective nature and small sample size that preclude the conclusions on the ICI‐induced phenomena of pseudo‐ and hyperprogression. Future studies with additional imaging that assesses the perfusion in brain tissues (e.g., positron emission tomography or MRI perfusion) may allow to discern inflammatory responses from disease progression in these patients. 7
The retrospective design of this pilot study precludes the definitive differentiation of the ICI‐induced encephalopathy in all patients. Given that spinal fluid was obtained only in a few patients, an infectious encephalitis causing altered mental status could have been missed. Furthermore, despite the stability of the CNS tumors prior to initiation of the ICI therapy, it is possible that in some patients the change in tumor size was due to the progression of disease rather than the effects of ICIs. This limitation may weaken the results of this comparative study. The lack of differences between other clinical parameters in patients with and without tumor could have not been detected because of the small sample size. Furthermore, the generalizability of these results to other hospital settings may be limited because of the small number of subjects and the study site being a tertiary care center. None of the patients included in the report had an autopsy which limits the determination of an actual cause of death. While this adds to the limitations to the study it further underscores the lack of recognition of potential complications of immunotherapy leading to rapid demise in patients with cancer.
Our findings indicate that, in patients with mental status changes during the ICI therapy at our center, prompt assessment for ICI‐related causes of encephalopathy was largely not completed and neurologists were rarely participating in the management of encephalopathy. Further, the majority of patients did not receive immunosuppressive therapy to reverse the symptoms of encephalopathy. This was particularly relevant to the management of patients 5 and more years ago when the awareness of ICI‐induced neurotoxicity was lacking. The evaluation and management decisions for these patients were made according to the existing standards of clinical care prior to the publication of the National Comprehensive Cancer Network consensus guidelines in 2019. 17 For example, the relevant recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group released in 2017 did not include EEG in the required diagnostic steps in suspected ICI‐related neurotoxicity. 18 Given that ICIs are frequently being incorporated into treatment protocols of cancer patients, providers need to be aware of the potential risk of encephalopathy and be familiar with the appropriate workup. For patients suspected of having CNS toxicity related to the ICI, a consultation with clinician with neurology expertise and knowledge of the field of ICIs, brain imaging as well as serum and CSF analysis for the presence of autoantibodies should be requested. 5 EEG should be obtained to exclude seizure activity. If a serious CNS toxicity is confirmed, the offending agent must be discontinued and specific immunotherapies be administered, including steroids, IVIG, and rituximab.
5 ETHICS APPROVAL STATEMENT
Retrospective chart review and analysis were conducted with the approval of the Institutional Review Board at the University of Nebraska Medical Center.
CONFLICT OF INTEREST
The authors have no relevant conflict of interest to disclose.
AUTHOR CONTRIBUTIONS
Danmeng Wei designed the study, collected the data, and drafted the manuscript for intellectual content. Daniel Zhou collected the data, performed the statistical analysis, and revised manuscript for intellectual content. Proleta Datta analyzed the data and revised manuscript for intellectual content. Olga Taraschenko directed the acquisition of data, interpreted the data, and revised manuscript for intellectual content.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGMENTS
None.
DATA AVAILABILITY STATEMENT
All available data are included in the manuscript. | Recovering | ReactionOutcome | CC BY | 33660430 | 19,057,138 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | DULOXETINE, PREGABALIN | DrugsGivenReaction | CC BY-NC-ND | 33661857 | 19,174,329 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyponatraemia'. | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | DULOXETINE, METFORMIN HYDROCHLORIDE, PREGABALIN | DrugsGivenReaction | CC BY-NC-ND | 33661857 | 19,181,470 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intracranial pressure increased'. | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | DULOXETINE, METFORMIN HYDROCHLORIDE, PREGABALIN | DrugsGivenReaction | CC BY-NC-ND | 33661857 | 19,181,470 | 2021-03-04 |
What is the weight of the patient? | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | 47 kg. | Weight | CC BY-NC-ND | 33661857 | 19,025,715 | 2021-03-04 |
What was the outcome of reaction 'Drug ineffective'? | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33661857 | 19,174,329 | 2021-03-04 |
What was the outcome of reaction 'Hyponatraemia'? | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33661857 | 19,181,470 | 2021-03-04 |
What was the outcome of reaction 'Inappropriate antidiuretic hormone secretion'? | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33661857 | 19,174,329 | 2021-03-04 |
What was the outcome of reaction 'Intracranial pressure increased'? | Successful Treatment with Percutaneous Balloon Kyphoplasty for Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Vertebral Compression Fracture: A Case Report.
BACKGROUND The etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH) is highly variable. With little evidence, much of the guidance and recommendations available for management are based on clinical judgement. Although percutaneous balloon kyphoplasty can effectively relieve the severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown. CASE REPORT A 72-year-old woman was admitted to our hospital due to severe pain associated with lumbar compression fracture and pain-related SIADH. Since her pain could not be relieved by analgesics, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. After the surgery, the patient's pain almost completely disappeared and her sodium level was gradually corrected within 3 days without any adverse events. CONCLUSIONS Percutaneous balloon kyphoplasty is a novel treatment option for SIADH associated with vertebral compression fracture. In the case presented here, it rapidly reduced pain and disability and also improved severe pain-associated SIADH without adverse effects. It may offer an alternative to pain regimens consisting of drugs, such as duloxetine, pregabalin, and opioids, that may exacerbate SIADH and hyponatremia. This case suggests treatment for new-onset or worsening hyponatremia in patients with vertebral compression fracture.
Background
Hyponatremia is a common electrolyte disturbance in clinical practice, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent condition underlying hyponatremia [1]. SIADH is characterized by abnormal release of antidiuretic hormone (ADH) or enhanced action of ADH on the kidney. The causative factors of SIADH include a wide variety of symptoms, diseases, and drugs [2]. There are a variety of management approaches for SIADH in clinical practice, but the evidence supporting their use is limited [3]. Percutaneous balloon kyphoplasty can effectively relieve severe pain associated with osteoporotic vertebral compression fractures that do not respond to conventional treatments, and it may help decrease the physical consequences related to fracture [4,5]. However, the effect of balloon kyphoplasty on SIADH associated with vertebral compression fracture remains unknown.
We report a case of SIADH associated with lumbar compression fracture in a patient who subsequently underwent percutaneous balloon kyphoplasty. We discuss the pathogenesis of SIADH in our case, as well as the perioperative management and treatment strategy for hyponatremia in SIADH associated with lumbar compression fracture.
Case Report
A 72-year-old woman was transferred to our hospital for the evaluation and treatment of severe lower back pain and radiating pain in the left leg. Although no significant traumatic event occurred, she experienced severe and worsening back pain and leg pain for 1 week before her transfer. Upon arrival, the patient rated her pain as 10/10 on a visual analog scale (VAS), where 0 indicated “no pain” and 10 indicated “worst pain.” She described her pain as stabbing, and it was exacerbated by movement of the axial spine. She experienced pain radiating toward the left lower extremity, but she had no problems with bowel and bladder function. Magnetic resonance imaging of the spine showed low intensity in a T1-weighted image and high intensity in a T2-weighted image at L5 (Figure 1A). Computed tomography myelography did not show compressive lesions pressing against the nerve roots or spinal cord (Figure 1B). An L5 osteoporotic vertebral compression fracture was diagnosed. The patient’s medical history was significant for type 2 diabetes mellitus and hypertension, but otherwise, she had no remarkable history. Her medications included metformin, angiotensin II receptor blockers, and Ca-channel blocker, but not any diuretics. On the fourth day of admission, a preoperative evaluation was conducted to determine whether pain relief surgery could be safely performed. The patient’s vital signs were as follows: height, 155.0 cm; weight, 47.0 kg without recent changes; temperature, 36.7°C; blood pressure, 116/65 mmHg; and pulse, 80 beats/min, with a regular sinus rhythm. Physical examination was also performed, and the findings were as follows. Her skin was moist, the heart sounds were normal with no murmurs, the lungs were clear without rales, and the lower extremities showed no signs of edema. Neurological examination findings were normal. The patient rated her pain as 9–10/10 on VAS. Clinical chemistry showed moderate hyponatremia (Na 125 mEq/L), hypo-osmolality (262 mOsm/kg), and hyperglycemia (fasting glucose, 176 mg/dL). Endocrine studies showed elevated ADH (1.6 pg/mL) and normal thyroid and adrenal gland function. Urinary sodium concentration was increased (56 mEq/L), and urinary osmolality was 410 mOsm/kg. Chest X-ray, electrocardiogram, and chest computed tomography findings upon admission were normal. The patient exhibited hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and absence of other potential causes of plasma hypo-osmolality, which indicated SIADH. Pregabalin for severe pain was initially suspected as the cause of SIADH. As the patient’s pain remained uncontrolled, pregabalin treatment was continued. Figure 2 shows the patient’s clinical course. The patient was initially instructed to restrict water intake (750 mL/d) and take salt tablets (54 mEq/d). However, the sodium level decreased after duloxetine was added to the patient’s treatment for severe pain. The patient’s pain was slightly relieved after addition of duloxetine, but she still rated it as 8–9/10 on VAS. As the patient refused opioids, duloxetine was continued. On the sixth day, she had nausea and mild agitation possibly due to increased intracranial pressure, and hypertonic saline infusion was started to treat her worsening hyponatremia. On the eighth day, she underwent percutaneous balloon kyphoplasty, a minimally invasive procedure intended to relieve pain. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. On the 10th day, the patient’s pain was rated as 0–2/10 on VAS. After pain relief surgery, hyponatremia and other findings improved spontaneously (Figure 2). On the 11th day, duloxetine was discontinued. The sodium level during a 6-month follow-up was within the normal range, although the patient continued to take only pregabalin.
Discussion
SIADH is a clinical syndrome of euvolemic hyponatremia [6]. Our patient showed hyponatremia, plasma hypo-osmolality, inappropriate urinary concentration at some level of plasma hypo-osmolality, elevated urinary sodium excretion, and normal function of the thyroid and adrenal glands, which indicated SIADH [7].
Our case encompasses 2 main concerns. The first involves the pathogenesis of SIADH. ADH plays an important part in the development of SIADH. Abnormal release of ADH or enhanced action of ADH on the kidney induces SIADH. In our case, plasma ADH concentrations were measured with a radioimmuno-assay kit (YAMASA Shoyu Corporation, Choshi, Japan) using a primary rabbit polyclonal antibody (interassay coefficient of variation [CV], 2.3–6.7%; intra-assay CV, 4.0–8.0%) and ADH was detectable in the setting of plasma hypo-osmolality, which suggested relative ADH elevation [8]. Given that hyponatremia in our patient worsened after treatment with duloxetine and pregabalin, yet it spontaneously resolved after pain relief surgery despite the patient continuing to take the medications, severe pain may stimulate ADH secretion. However, duloxetine and pregabalin may induce or worsen hyponatremia, more so in presence of predisposing factors like advanced age and pain. We cannot elucidate the mechanisms underlying the development of SIADH in the present case; however, the stimulation of hypothalamus, which is one of the pain modulation sites, might affect ADH secretion [9]. ADH secretion may also be increased by duloxetine through the stimulation of the serotonin and norepinephrine receptors in the hypothalamus [10,11]. Pregabalin-induced SIADH has rarely been reported, and the pathogenesis remains unknown [12]. However, measurement of ADH may be clinically of little value because plasma ADH is elevated in both hypovolemic and hypervolemic hyponatremia, and it might be difficult to measure accurately because of the difficult of handling, storing, and assaying samples [6].
The second concern is the treatment strategy for SIADH associated with vertebral compressive fractures. Various treatment approaches for SIADH have been recommended in different countries and organizations, yet they lack strong evidence in support of their use [13]. Common treatment options include fluid restriction, the management of the underlying disorder, and the discontinuation of the offending medication, but some patients with SIADH require other options. Percutaneous balloon kyphoplasty may be a novel treatment option for SIADH associated with vertebral compression fracture. It not only rapidly reduced pain and disability in the current case but also improved severe pain-associated SIADH without adverse effects [3,4]. Percutaneous balloon kyphoplasty may offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Our experience centered on the perioperative management of a patient with SIADH-related hyponatremia who underwent pain relief surgery. A recent cohort study showed that preoperative hyponatremia was a prognostic marker for morbidity and mortality, but the effectiveness and safety of the intervention for preoperative hyponatremia have not yet been established [14]. However, a dynamic change in sodium level may increase the risk for several adverse outcomes such as postoperative pneumonia, renal failure, and central pontine myelinolysis [15]. Therefore, we carefully monitored the patient’s sodium level to avoid overcorrection after surgery. Postoperative rapid diuresis did not occur, and the sodium level was gradually corrected within 3 days. SIADH induced by severe pain slowly resolved after pain relief surgery. This phenomenon might reflect the pathogenesis of SIADH induced by pain, which can stimulate ADH secretion. This case could help clinicians treat new-onset or worsening hyponatremia in patients with a vertebral compression fracture.
Conclusions
We report a case of SIADH associated with lumbar compression fracture in a patient who underwent balloon kyphoplasty for pain relief. In case of SIADH associated with a vertebral compression fracture, percutaneous balloon kyphoplasty might offer an alternative to pain regimens consisting of drugs that may further worsen SIADH and hyponatremia.
Figure 1. (A) Sagittal lumbar magnetic resonance image displaying a fracture with associated edema on L5. The arrow indicates the fracture. (B) Sagittal computed tomography myelography did not show compressive lesions pressing against the nerve roots and spinal cord.
Figure 2. Clinical course of our patient. The image shows the change in serum sodium level in relation to the administration of pregabalin and duloxetine. Hyponatremia gradually resolved after pain relief surgery. VAS – visual analog scale.
Conflict of Interests
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33661857 | 19,181,470 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delirium'. | Delirium caused by topical administration of cyclopentolate for cataract surgery in mild cognitive impairment due to Alzheimer's disease: A case report.
Cholinergic modification by anticholinergic medication can produce adverse effects in central nervous system (CNS) and cyclopentolate is an antimuscarinic agent widely used for ophthalmologic management. We demonstrate a rare case of hyperactive delirium caused by topical administration of cyclopentolate in a patient with amnestic mild cognitive impairment (MCI) due to Alzheimer's disease (AD).
A 74-year-old man showed acute confusion after preparation for cataract operation in day surgery clinic. The patient became confused and agitated after instillation of topical cyclopentolate drop into the eye and the symptoms persisted over several hours.
METHODS
Previously the patient had been diagnosed with amnestic MCI with the finding of bilateral medial temporal atrophy on brain magnetic resonance imaging. 18F-flutemetamol positron emission tomography scan demonstrated multifocal amyloid deposition in the brain.
METHODS
The patient was closely observed with the supportive management.
RESULTS
The patient began to recover 5 h after the onset of symptoms and the cognitive function was reverted to previous state within 24 h.
CONCLUSIONS
It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient who is diagnosed with MCI due to AD in this case.
1 Introduction
The cholinergic system is widely distributed in the brain and plays an important role in cognitive functions such as attention, information processing, memory, and learning. Cholinergic modification by anticholinergic medication can result in anticholinergic syndrome in central nervous system (CNS) that includes cognitive decline, psychosis, seizure, and a variety of neurologic signs. Cyclopentolate is an antimuscarinic agent as mydriatics and cycloplegics and widely used for ophthalmologic examination and surgery with the benefit of rapid onset and recovery. Although CNS adverse event of topical anticholinergic agents is not common, several cases related CNS manifestation after instillation of topical eye drops have been reported.[1,2] We describe a case of hyperactive delirium that developed after the topical application of cyclopentolate for cataract surgery in a patient with amnestic mild cognitive impairment due to Alzheimer's disease (AD).
2 Case report
A 74-year-old, right-handed Asian man with 4 years of education was admitted to ophthalmology clinic for cataract refractive surgery. The patient suffered episodic memory decline over the past 3 years and prior neuropsychological assessment performed 2 years before this visit revealed low performance in memory on the Seoul Verbal Learning Test that was 3%tile score below 1.5 standard deviations from the mean of the age and education-normative values among the Korean population. The patient was not impaired in other cognitive domains. Magnetic resonance imaging (MRI) of the brain showed atrophic changes in the whole brain and bilateral medial temporal lobes and focal chronic infarction in the right cerebellum (Fig. 1A). The patient had been diagnosed with amnestic mild cognitive impairment (MCI) and regularly followed up for the state. The cognitive status was stable over 2 years. The patient had hypertension, diabetes mellitus, and dyslipidemia. Before the cataract operation, one drop of 1.0% of cyclopentolate was administered to patient's eyes. One hour after the instillation of eye drop, the patient got confused and showed abnormal behavior. The patient tried to remove the peripheral venous line and became aggressive to medical staff. The patient was referred to Department of Neurology and the elemental neurological examination revealed no abnormality. Two hours after the event, the Korean version of Mini-Mental State Examination (K-MMSE) was performed and the score was 16 of 30 which had been 26 of 30 on previous test. The patient began to recover 5 h after the onset of symptoms and the cognitive function was reverted to previous state within 24 h. 18F-flutemetamol positron emission tomography (PET) scan performed 2 months after the event demonstrated multifocal amyloid deposits in bilateral frontal lobes, the left precuneus, and the right lateral temporal cortex (Fig. 1Band C).
Figure 1 Brain MRI revealed bilateral medial temporal atrophy on coronal plane (A). 18F-flutemetamol PET scan demonstrated amyloid accumulation in bilateral frontal lobes (B) and precuneus (C). MRI = magnetic resonance imaging, PET = positron emission tomography.
3 Discussion
The transient manifestations of the patient which developed after receiving eye drops of cyclopentolate include confusion, agitation, and aggressiveness and lead to diagnosis of hyperactive delirium. The patient had been diagnosed with amnestic MCI which is a syndrome defined by clinical, cognitive, and functional criteria.
It has been well known that anticholinergics has a detrimental effect on cognitive functions. Cholinergic deficiency is recognized as a likely contributing feature to all cause of delirium.[3] The amount of anticholinergic burden in the normal elderly is closely related to cognitive impairment in memory and executive functions and brain atrophy measured by whole brain cortical volume, temporal cortical thickness, and lateral inferior temporal volume.[4] Cyclopentolate is a synthetic anticholinergic agent which produce mydriasis and cycloplegia with the benefit of rapid onset and recovery. Cyclopentolate eyedrops pass readily through nasolacrimal duct and are well absorbed locally as well as systemically via conjunctiva and nasal mucosa.[5] Systemic toxicity includes inappropriate behavior, visual and auditory hallucinations, and cerebellar dysfunction that has been reported mostly in a group of children and adolescents and depends on the dose administered.[2] It has been reported that instillation of several drops of a solution of cyclopentolate produced mental deterioration in an elderly patient with dementia.[1] In this case, we demonstrated the exact neurological status of the patient who suffered mild cognitive decline and showed amyloid accumulation in the brain on PET imaging which suggests underlying pathophysiologic process. Cholinergic deficit can make the elderly with MCI or dementia more vulnerable than the cognitively normal persons to cognitive impairment. Nonetheless, there may be some possible limitations in this study. The causal relationship between delirium and the drug and the exact mechanism may not be clear. The lowest available concentration of the cyclopentolate should be applied for prevention of systemic toxicity especially in patients with cognitive decline.[2]
MCI has been known to be transitional state between the cognitive changes of normal aging and dementia but is a heterogeneous clinical condition with several subtypes and multiple etiologies. But the patient showed PET evidence of Aβ deposition in the brain and structural MRI findings for neuronal injury that suggest AD pathophysiological processes in cognitive decline which led to the diagnosis of MCI due to AD. It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient with prodromal AD in this case.
Author contributions
Conceptualization: Hak Young Rhee.
Data curation: Yu Yong Shin.
Writing – original draft: Yu Yong Shin.
Writing – review & editing: Jin San Lee, Key-Chung Park, Hak Young Rhee.
Abbreviations: AD = Alzheimer's disease, CNS = central nervous system, MCI = mild cognitive impairment, MRI = magnetic resonance imaging, PET = positron emission tomography.
How to cite this article: Shin YY, Lee JS, Park KC, Rhee HY. Delirium caused by topical administration of cyclopentolate for cataract surgery in mild cognitive impairment due to Alzheimer's disease: a case report. Medicine. 2021;100:8(e24394).
All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from the patient for publication of the case details and accompanying images.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the present study. | CYCLOPENTOLATE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33663052 | 19,047,004 | 2021-02-26 |
What was the administration route of drug 'CYCLOPENTOLATE HYDROCHLORIDE'? | Delirium caused by topical administration of cyclopentolate for cataract surgery in mild cognitive impairment due to Alzheimer's disease: A case report.
Cholinergic modification by anticholinergic medication can produce adverse effects in central nervous system (CNS) and cyclopentolate is an antimuscarinic agent widely used for ophthalmologic management. We demonstrate a rare case of hyperactive delirium caused by topical administration of cyclopentolate in a patient with amnestic mild cognitive impairment (MCI) due to Alzheimer's disease (AD).
A 74-year-old man showed acute confusion after preparation for cataract operation in day surgery clinic. The patient became confused and agitated after instillation of topical cyclopentolate drop into the eye and the symptoms persisted over several hours.
METHODS
Previously the patient had been diagnosed with amnestic MCI with the finding of bilateral medial temporal atrophy on brain magnetic resonance imaging. 18F-flutemetamol positron emission tomography scan demonstrated multifocal amyloid deposition in the brain.
METHODS
The patient was closely observed with the supportive management.
RESULTS
The patient began to recover 5 h after the onset of symptoms and the cognitive function was reverted to previous state within 24 h.
CONCLUSIONS
It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient who is diagnosed with MCI due to AD in this case.
1 Introduction
The cholinergic system is widely distributed in the brain and plays an important role in cognitive functions such as attention, information processing, memory, and learning. Cholinergic modification by anticholinergic medication can result in anticholinergic syndrome in central nervous system (CNS) that includes cognitive decline, psychosis, seizure, and a variety of neurologic signs. Cyclopentolate is an antimuscarinic agent as mydriatics and cycloplegics and widely used for ophthalmologic examination and surgery with the benefit of rapid onset and recovery. Although CNS adverse event of topical anticholinergic agents is not common, several cases related CNS manifestation after instillation of topical eye drops have been reported.[1,2] We describe a case of hyperactive delirium that developed after the topical application of cyclopentolate for cataract surgery in a patient with amnestic mild cognitive impairment due to Alzheimer's disease (AD).
2 Case report
A 74-year-old, right-handed Asian man with 4 years of education was admitted to ophthalmology clinic for cataract refractive surgery. The patient suffered episodic memory decline over the past 3 years and prior neuropsychological assessment performed 2 years before this visit revealed low performance in memory on the Seoul Verbal Learning Test that was 3%tile score below 1.5 standard deviations from the mean of the age and education-normative values among the Korean population. The patient was not impaired in other cognitive domains. Magnetic resonance imaging (MRI) of the brain showed atrophic changes in the whole brain and bilateral medial temporal lobes and focal chronic infarction in the right cerebellum (Fig. 1A). The patient had been diagnosed with amnestic mild cognitive impairment (MCI) and regularly followed up for the state. The cognitive status was stable over 2 years. The patient had hypertension, diabetes mellitus, and dyslipidemia. Before the cataract operation, one drop of 1.0% of cyclopentolate was administered to patient's eyes. One hour after the instillation of eye drop, the patient got confused and showed abnormal behavior. The patient tried to remove the peripheral venous line and became aggressive to medical staff. The patient was referred to Department of Neurology and the elemental neurological examination revealed no abnormality. Two hours after the event, the Korean version of Mini-Mental State Examination (K-MMSE) was performed and the score was 16 of 30 which had been 26 of 30 on previous test. The patient began to recover 5 h after the onset of symptoms and the cognitive function was reverted to previous state within 24 h. 18F-flutemetamol positron emission tomography (PET) scan performed 2 months after the event demonstrated multifocal amyloid deposits in bilateral frontal lobes, the left precuneus, and the right lateral temporal cortex (Fig. 1Band C).
Figure 1 Brain MRI revealed bilateral medial temporal atrophy on coronal plane (A). 18F-flutemetamol PET scan demonstrated amyloid accumulation in bilateral frontal lobes (B) and precuneus (C). MRI = magnetic resonance imaging, PET = positron emission tomography.
3 Discussion
The transient manifestations of the patient which developed after receiving eye drops of cyclopentolate include confusion, agitation, and aggressiveness and lead to diagnosis of hyperactive delirium. The patient had been diagnosed with amnestic MCI which is a syndrome defined by clinical, cognitive, and functional criteria.
It has been well known that anticholinergics has a detrimental effect on cognitive functions. Cholinergic deficiency is recognized as a likely contributing feature to all cause of delirium.[3] The amount of anticholinergic burden in the normal elderly is closely related to cognitive impairment in memory and executive functions and brain atrophy measured by whole brain cortical volume, temporal cortical thickness, and lateral inferior temporal volume.[4] Cyclopentolate is a synthetic anticholinergic agent which produce mydriasis and cycloplegia with the benefit of rapid onset and recovery. Cyclopentolate eyedrops pass readily through nasolacrimal duct and are well absorbed locally as well as systemically via conjunctiva and nasal mucosa.[5] Systemic toxicity includes inappropriate behavior, visual and auditory hallucinations, and cerebellar dysfunction that has been reported mostly in a group of children and adolescents and depends on the dose administered.[2] It has been reported that instillation of several drops of a solution of cyclopentolate produced mental deterioration in an elderly patient with dementia.[1] In this case, we demonstrated the exact neurological status of the patient who suffered mild cognitive decline and showed amyloid accumulation in the brain on PET imaging which suggests underlying pathophysiologic process. Cholinergic deficit can make the elderly with MCI or dementia more vulnerable than the cognitively normal persons to cognitive impairment. Nonetheless, there may be some possible limitations in this study. The causal relationship between delirium and the drug and the exact mechanism may not be clear. The lowest available concentration of the cyclopentolate should be applied for prevention of systemic toxicity especially in patients with cognitive decline.[2]
MCI has been known to be transitional state between the cognitive changes of normal aging and dementia but is a heterogeneous clinical condition with several subtypes and multiple etiologies. But the patient showed PET evidence of Aβ deposition in the brain and structural MRI findings for neuronal injury that suggest AD pathophysiological processes in cognitive decline which led to the diagnosis of MCI due to AD. It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient with prodromal AD in this case.
Author contributions
Conceptualization: Hak Young Rhee.
Data curation: Yu Yong Shin.
Writing – original draft: Yu Yong Shin.
Writing – review & editing: Jin San Lee, Key-Chung Park, Hak Young Rhee.
Abbreviations: AD = Alzheimer's disease, CNS = central nervous system, MCI = mild cognitive impairment, MRI = magnetic resonance imaging, PET = positron emission tomography.
How to cite this article: Shin YY, Lee JS, Park KC, Rhee HY. Delirium caused by topical administration of cyclopentolate for cataract surgery in mild cognitive impairment due to Alzheimer's disease: a case report. Medicine. 2021;100:8(e24394).
All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from the patient for publication of the case details and accompanying images.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the present study. | Ophthalmic | DrugAdministrationRoute | CC BY | 33663052 | 19,047,004 | 2021-02-26 |
What was the outcome of reaction 'Delirium'? | Delirium caused by topical administration of cyclopentolate for cataract surgery in mild cognitive impairment due to Alzheimer's disease: A case report.
Cholinergic modification by anticholinergic medication can produce adverse effects in central nervous system (CNS) and cyclopentolate is an antimuscarinic agent widely used for ophthalmologic management. We demonstrate a rare case of hyperactive delirium caused by topical administration of cyclopentolate in a patient with amnestic mild cognitive impairment (MCI) due to Alzheimer's disease (AD).
A 74-year-old man showed acute confusion after preparation for cataract operation in day surgery clinic. The patient became confused and agitated after instillation of topical cyclopentolate drop into the eye and the symptoms persisted over several hours.
METHODS
Previously the patient had been diagnosed with amnestic MCI with the finding of bilateral medial temporal atrophy on brain magnetic resonance imaging. 18F-flutemetamol positron emission tomography scan demonstrated multifocal amyloid deposition in the brain.
METHODS
The patient was closely observed with the supportive management.
RESULTS
The patient began to recover 5 h after the onset of symptoms and the cognitive function was reverted to previous state within 24 h.
CONCLUSIONS
It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient who is diagnosed with MCI due to AD in this case.
1 Introduction
The cholinergic system is widely distributed in the brain and plays an important role in cognitive functions such as attention, information processing, memory, and learning. Cholinergic modification by anticholinergic medication can result in anticholinergic syndrome in central nervous system (CNS) that includes cognitive decline, psychosis, seizure, and a variety of neurologic signs. Cyclopentolate is an antimuscarinic agent as mydriatics and cycloplegics and widely used for ophthalmologic examination and surgery with the benefit of rapid onset and recovery. Although CNS adverse event of topical anticholinergic agents is not common, several cases related CNS manifestation after instillation of topical eye drops have been reported.[1,2] We describe a case of hyperactive delirium that developed after the topical application of cyclopentolate for cataract surgery in a patient with amnestic mild cognitive impairment due to Alzheimer's disease (AD).
2 Case report
A 74-year-old, right-handed Asian man with 4 years of education was admitted to ophthalmology clinic for cataract refractive surgery. The patient suffered episodic memory decline over the past 3 years and prior neuropsychological assessment performed 2 years before this visit revealed low performance in memory on the Seoul Verbal Learning Test that was 3%tile score below 1.5 standard deviations from the mean of the age and education-normative values among the Korean population. The patient was not impaired in other cognitive domains. Magnetic resonance imaging (MRI) of the brain showed atrophic changes in the whole brain and bilateral medial temporal lobes and focal chronic infarction in the right cerebellum (Fig. 1A). The patient had been diagnosed with amnestic mild cognitive impairment (MCI) and regularly followed up for the state. The cognitive status was stable over 2 years. The patient had hypertension, diabetes mellitus, and dyslipidemia. Before the cataract operation, one drop of 1.0% of cyclopentolate was administered to patient's eyes. One hour after the instillation of eye drop, the patient got confused and showed abnormal behavior. The patient tried to remove the peripheral venous line and became aggressive to medical staff. The patient was referred to Department of Neurology and the elemental neurological examination revealed no abnormality. Two hours after the event, the Korean version of Mini-Mental State Examination (K-MMSE) was performed and the score was 16 of 30 which had been 26 of 30 on previous test. The patient began to recover 5 h after the onset of symptoms and the cognitive function was reverted to previous state within 24 h. 18F-flutemetamol positron emission tomography (PET) scan performed 2 months after the event demonstrated multifocal amyloid deposits in bilateral frontal lobes, the left precuneus, and the right lateral temporal cortex (Fig. 1Band C).
Figure 1 Brain MRI revealed bilateral medial temporal atrophy on coronal plane (A). 18F-flutemetamol PET scan demonstrated amyloid accumulation in bilateral frontal lobes (B) and precuneus (C). MRI = magnetic resonance imaging, PET = positron emission tomography.
3 Discussion
The transient manifestations of the patient which developed after receiving eye drops of cyclopentolate include confusion, agitation, and aggressiveness and lead to diagnosis of hyperactive delirium. The patient had been diagnosed with amnestic MCI which is a syndrome defined by clinical, cognitive, and functional criteria.
It has been well known that anticholinergics has a detrimental effect on cognitive functions. Cholinergic deficiency is recognized as a likely contributing feature to all cause of delirium.[3] The amount of anticholinergic burden in the normal elderly is closely related to cognitive impairment in memory and executive functions and brain atrophy measured by whole brain cortical volume, temporal cortical thickness, and lateral inferior temporal volume.[4] Cyclopentolate is a synthetic anticholinergic agent which produce mydriasis and cycloplegia with the benefit of rapid onset and recovery. Cyclopentolate eyedrops pass readily through nasolacrimal duct and are well absorbed locally as well as systemically via conjunctiva and nasal mucosa.[5] Systemic toxicity includes inappropriate behavior, visual and auditory hallucinations, and cerebellar dysfunction that has been reported mostly in a group of children and adolescents and depends on the dose administered.[2] It has been reported that instillation of several drops of a solution of cyclopentolate produced mental deterioration in an elderly patient with dementia.[1] In this case, we demonstrated the exact neurological status of the patient who suffered mild cognitive decline and showed amyloid accumulation in the brain on PET imaging which suggests underlying pathophysiologic process. Cholinergic deficit can make the elderly with MCI or dementia more vulnerable than the cognitively normal persons to cognitive impairment. Nonetheless, there may be some possible limitations in this study. The causal relationship between delirium and the drug and the exact mechanism may not be clear. The lowest available concentration of the cyclopentolate should be applied for prevention of systemic toxicity especially in patients with cognitive decline.[2]
MCI has been known to be transitional state between the cognitive changes of normal aging and dementia but is a heterogeneous clinical condition with several subtypes and multiple etiologies. But the patient showed PET evidence of Aβ deposition in the brain and structural MRI findings for neuronal injury that suggest AD pathophysiological processes in cognitive decline which led to the diagnosis of MCI due to AD. It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient with prodromal AD in this case.
Author contributions
Conceptualization: Hak Young Rhee.
Data curation: Yu Yong Shin.
Writing – original draft: Yu Yong Shin.
Writing – review & editing: Jin San Lee, Key-Chung Park, Hak Young Rhee.
Abbreviations: AD = Alzheimer's disease, CNS = central nervous system, MCI = mild cognitive impairment, MRI = magnetic resonance imaging, PET = positron emission tomography.
How to cite this article: Shin YY, Lee JS, Park KC, Rhee HY. Delirium caused by topical administration of cyclopentolate for cataract surgery in mild cognitive impairment due to Alzheimer's disease: a case report. Medicine. 2021;100:8(e24394).
All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from the patient for publication of the case details and accompanying images.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the present study. | Recovered | ReactionOutcome | CC BY | 33663052 | 19,047,004 | 2021-02-26 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Carbon dioxide: the cause of devastating stroke without hemodynamic compromise during laparoscopic nephrectomy with injury of the inferior vena cava: A case report.
BACKGROUND
Carbon dioxide pneumoperitoneum in laparoscopic surgery can bring about occult perioperative cerebral infarction, advancing our understanding of the causes of severe postoperative delayed recovery.
Here, we report the case of a 35-year-old woman who underwent a right renal tumor resection in our institution, during which a raised pneumoperitoneum pressure (from 15 to 20 mm Hg) was adopted by the surgeon to prevent errhysis and to help stop the bleeding. Despite an accidental minor tearing of the inferior vena cava, vital signs remained stable throughout the procedure, and no obvious abnormality was observed in either end tidal carbon dioxide values or blood gas analysis. However, the patient unexpectedly suffered delayed recovery after the operation, presenting incomplete left hemiplegia and a positive Babinski sign.
Perioperative stroke was diagnosed by anesthesiologists, after excluding the effects of anesthesia. Cerebral hemorrhage was excluded, as no obvious abnormality was found in the density of brain parenchyma in the emergency computed tomography examination, and a digital subtraction angiography showed no abnormal thrombosis. Further magnetic resonance diagnosis led us to consider diffuse gas embolisms to be the cause of this acute stroke; a right echocardiography revealed that a patent foramen ovale (PFO) may account for the global cerebral gas embolisms.
METHODS
The patient received neuroprotective drugs (Vinpocetine, Edaravone, and Xingnaojing, which are commonly used as a standard of care in China), antiplatelets and other symptomatic treatments, plus dexamethasone to relieve edema. A contrast-enhanced echocardiography of the right heart was performed, the results of which were consistent with the sonography of a PFO.
RESULTS
The patient was hospitalized for 14 days and eventually discharged after recovery. At the latest follow-up in August 2019, the patient recovered without residual neurological sequelae.
CONCLUSIONS
Our results emphasize the need for vigilance regarding adverse cardiovascular and neurological events caused by carbon dioxide gas embolisms when encountering the inadvertent situation of vessels rupturing. Timely monitoring of paradoxical gas embolism by transoesophageal echocardiography is necessary and can avert the risk of severe complications. Urgent consideration should be given to stopping pneumoperitoneum and switching to laparotomy for hemostasis so that the patient can obtain the best benefit-risk ratio.
1 Introduction
Laparoscopic tumor resection is becoming increasingly popular among patients and surgeons due to its minimal invasiveness, clear vision, and fast postoperative recovery. Carbon dioxide is generally used for pneumoperitoneum, which is safe because of its high solubility in the blood, and its tendency not to produce gas embolism. Only when a large amount of carbon dioxide enters the circulatory system will embolism occur, with a very low incidence of about 0.15%.[1] In the process of tumor separation, occasional small lacerations of blood vessels are inevitable, resulting in a blurred visual field due to oozing blood. At such moments, is it appropriate to use pneumoperitoneum pressure to stop the bleeding and to continue the operation via laparoscopy? According to research reports, the first response of surgeons is that a certain degree of pneumoperitoneum pressure can help stop the bleeding,[2–4] but this will in turn increase the incidence of gas embolism[5] and also increase the complexity of perioperative management. Under these circumstances, carbon dioxide will be absorbed into the blood at pneumoperitoneum pressure, which will not only cause subcutaneous emphysema and delayed recovery (carbon dioxide anesthesia), but also damage to important organs, for example, heart, lungs, and brain, and even occasionally pulmonary embolism or paradoxical gas embolism.[6] This kind of gas embolism complication is rare but usually fatal, with a high probability of cardiac arrest,[7] which is usually accompanied by hemodynamic instability, a sharp drop in blood pressure, and a decrease[8] in end tidal carbon dioxide (ETCO2) values. However, paradoxical gas embolism causing cerebral infarction in laparoscopic surgery may still occur without observable abnormalities in blood pressure, CO2, and blood gas analysis, which is even rarer; to date no relevant report exists of such a case. Here, we report a case of occult cerebral infarction during retroperitoneal laparoscopic renal tumor resection with a minor tearing of the inferior vena cava, which was only identified due to severe delayed recovery.
2 Case presentation
The report was approved by the ethics review board of Peking University Third Hospital and was CARE compliant. Informed consent for publication was obtained from the patient.
The patient, a 35-year-old female (height 165 cm, weight 64 kg), was admitted to hospital due to flank pain persisting for more than 1 month, and was diagnosed with right renal carcinoma. It was therefore proposed to perform a laparoscopic right renal tumor resection under general anesthesia. The patient's previous medical history includes appendectomy and ectopic pregnancy surgery, and penicillin allergy. She had no communicable diseases, for example, hepatitis, tuberculosis, malaria; no history of hypertension, diabetes, and cardiac or cerebrovascular diseases; and no episodes of mental illness, trauma, blood transfusions, or food allergies. All preoperative evaluation tests, including routine blood, routine coagulation function, liver and kidney function, Electrocardiogram (ECG) and chest radiograph, were unremarkable. General anesthesia was induced using sufentanil 30 μg, etomidate 12 mg, propofol 80 mg, and rocuronium 50 mg, monitoring pulse oxygen saturation, capnography, ECG and invasive arterial blood pressure, and was maintained using a mixture of O2 1 L/min, air 1 L/min, sevoflurane 1.5 to 2.0 vol %, and remifentanil 0.05 to 0.2 μg/kg/min. The left lateral decubitus position is employed to facilitate the surgery.
Thirty minutes after the beginning of the surgery, the pneumoperitoneum pressure was increased (15–20 mm Hg) to help stop bleeding. At this point, ETCO2 was 41 mm Hg. During the procedure, an accidental minor tearing of the inferior vena cava occurred. A gauze compression was used to stop the bleeding, and the rupture was sutured as quickly as possible. ETCO2 (41–47 mm Hg) and invasive blood pressure were stable (118–145/65–79 mm Hg) during the process, and there were no obvious abnormal observations, except for the heart rate, which had a period of fluctuation (range 45–120 times/min); but then returned to normal with no specific treatment. Arterial blood gas analysis: pH = 7.30, PaCO2 = 48 mm Hg, PaO2 = 455 mm Hg, K+ = 3.2 mmol/L, Ca2+ = 1.13 mmol/L, HCO3- = 21.1 mmol/L, Glucose = 4.2 mmol/L, Base Excess = −3.8 mmol/L, Hb = 125 g/L, SaO2 = 100%. Anesthesiologists provided potassium supplement, increased the respiration rate of mechanical ventilation, and continued to observe without any further treatment. Subsequently, all indicators were stable and the operation was successfully completed. The bleeding volume was 50 mL, the urine output and the total input volumes were 100 and 2600 mL, respectively.
The patient was admitted to the post anesthesia care unit (PACU) and resumed regular spontaneous breathing (tidal volume > 400 mL, respiratory rate 16 times/min), was deoxidized for 10 min (SpO2 > 95%), and was then extubated after an intravenous injection of atropine 0.5 mg+ neostigmine 1 mg. After extubation, the patient had stable vital signs and normal spontaneous breathing, but woke up only after 2 hours, gazing to the left. She was unable to communicate, with poor recovered consciousness and frequent vomiting. Blood gas analysis in PACU: pH = 7.37, PaCO2 = 38 mm Hg, PaO2 = 114 mm Hg, K+ = 3.5 mmol/L, Ca2+ = 1.16 mmol/L, HCO3- = 21.4 mmol/L, Glucose = 6.4 mmol/L, Base Excess = −3.4 mmol/L, Hb = 128 g/L, SaO2 = 98%. The patient was given 10 mg metoclopramide intravenously for nausea and vomiting. In terms of recovery of consciousness, the patient exhibited a frowning reflex on the right side of the face in response to the noxious stimuli, while the observed left facial movement was less, attracting the attention of the perioperative physician. The anesthesiologist believed that this was not an ordinary case of delayed awakening, and communicated with the urologist and asked the neurologist for an urgent consultation. The patient's left upper limb movement was poor, the left lower limb could not move, and the left Babinski sign was positive; thus, cerebral hemorrhage or infarction was suspected. Subsequently, a noncontrast head computed tomography (CT) in emergency was performed, with no obvious abnormality found in the brain parenchymal density (Fig. 1A), thus excluding cerebral hemorrhage. According to the signs and symptoms, acute cerebral infarction with intracranial artery occlusion was hypothesized. A further digital subtraction angiography was performed in the department of vascular intervention, to prepare for interventional catheter thrombectomy and thrombolysis. Unexpectedly, no clear embolism was identified in the whole cerebrovascular system (Fig. 1B). According to the signs and symptoms, the patient was initially diagnosed as acute life-threatening brain stem infarction and was transferred to intensive care unit, due to the possibility of sudden death because of compression in the medulla oblongata cardiovascular center during the peak period of cerebral edema after brain stem infarction. The patient was intubated again due to hypoxemia (SpO2 89%). CT re-examination on the second postoperative day revealed only that the density of brain parenchyma was less uniform than before, and a new patchy, low-density shadow was observed in the right basal ganglia and temporal occipital lobe (Fig. 1C). The patient did not show any improvement, despite receiving neuroprotective drugs (Vinpocetine, Edaravone, and Xingnaojing, which are commonly used as a standard of care in China), antiplatelets and other symptomatic treatments, for example, mannitol dehydration treatment to reduce intracranial pressure, sedation, anti-infection, plus dexamethasone to relieve edema at the same time. The patient subsequently awoke, with her left limb movement showing obvious signs of recovery, at which point the doctors decided to transfer her to another hospital for hyperbaric oxygen therapy.
Figure 1 The imaging examination. A, An emergency CT examination was performed. No obvious abnormality was found in the density of brain parenchyma. B, DSA angiography showed no obvious abnormality in the whole cerebral blood vessel network (the image is the angiography image of the right carotid system). C, CT was rechecked 2 days after surgery, and the density of brain parenchyma was found to be uneven. On the right side, new patchy and slightly low-density shadows are seen in the basal ganglia and temporal occipital lobe. On the 5th day postsurgery, MR showed multiple lesions in bilateral brain, cerebellum, and brainstem, more pronounced on the right side; DWI, Diffusion Weighted Imaging images showed multiple spot-like, patch-like, line-like, and nodule-like high signal shadows in the bilateral cerebrum (D), cerebellum (E), and brainstem (F), more pronounced on the right side. G, The echocardiography reexamined after the operation showed that the structure of the heart was basically normal, no signal of left to right shunt was detected in the middle of the atrial septum; no echo interruption was detected, the ventricular septum was continuous and complete, and there was no sign of patent ductus arteriosus. H, Contrast echocardiography of the right heart. 10 days after the operation, normal saline contrast agent (agitated saline mixed with air) was injected by left elbow vein, the images of the right atrium and right ventricle were sequentially completed. And a small amount of contrast signal (blue arrow) appeared in the left atrium and left ventricle after 3 cardiac cycles. I, The above process is repeated twice, with identical results: in the image, the mitral valve has opened, and a small amount of contrast signal has entered the left ventricle. DSA = digital subtraction angiography, DWI = diffusion weighted imaging, MR = magnetic resonance.
The patient recovered consciousness on the third postoperative day. She was able to move her right limb according to instructions; the left upper limb had less pain-stimulus activity, while the left lower limb had no obvious pain-stimulus activity. The left Babinski sign was still positive. To further clarify the cause, a subsequent brain MRI examination was carried out when the patient's vital signs were stable, which showed a diffuse macular shadow of the whole brain, with gas embolism the suspected cause (Fig. 1D–F). On the seventh day after surgery, the movement of left upper and lower limbs was obviously improved, muscle strength was grade 5, and the left positive Babinski sign had disappeared.
It is worth mentioning that at the time of cerebral infarction, the patient also suffered from myocardial ischemia injury. The postoperative biomarker N-terminal pro-brain natriuretic peptide, and myocardial injury markers troponin I and creatine kinase MB also increased, as shown in Table 1.
Table 1 Postoperative changes of myocardial biomarkers in the patient.
Cardiac biomarkers (reference range) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
NT-proBNP, pg/mL (12–133) 70 1060 2120 1350 339 238
TnI, ng/mL (0.01–0.023) 0.110 0.900 0.250 0.110 0.064 0.031
CK-MB, ng/mL (0.1–4.94) 10 40 2.80 <2.0 2.10 3.30
CK-MB = creatine kinase MB, NT-proBNP = N-terminal pro-brain natriuretic peptide, TnI = troponin I.
According to the images from the brain magnetic resonance examination, it was concluded that the cerebral infarction was caused by gas embolisms. To further determine the cause, transthoracic echocardiography was re-examined after the patient had recovered, and no obvious atrial septal defect, ventricular septal defect, or patent ductus arteriosus was identified (Fig. 1G). Following this, a right heart contrast-enhanced echocardiography was performed, the results of which were consistent with the sonographic findings (Fig. 1H, I) of a potential patent foramen ovale (PFO). The diagnosis was clear considering that the cerebral infarction was caused by gas embolisms passing through the PFO channel. The patient was hospitalized for 14 days and discharged after recovery. The patient was diagnosed as having right renal clear cell carcinoma according to the postoperative pathological report. At the latest follow-up in August 2019, the patient was in good health without obvious sequelae.
3 Discussion
According to the literature, cerebral infarction caused by air embolisms in the perioperative period is very rare.[9] Carbon dioxide embolization following vascular injury in minimally invasive endoscopic surgery is also a rare but often fatal complication,[8] generally accompanied by pulmonary embolism and cardiovascular collapse. If identified in time, the change will be made to open surgery. Successful rescue will not lead to further serious neurological complications. One widely described mechanism of gas embolism is venous embolic occlusion due to retrograde upward migration of gas bubbles; but the possibility is invalid, as the left lateral decubitus position was used for our patient, and the head position was not higher than the right atrium. In the initial CT images, there was no evidence of bubbles in the cerebral sinuses. We believe that PFO is the most likely way for the gas bubbles to enter the arterial system, which was later confirmed by a right heart contrast echocardiography. In this case, due to the potential PFO, a massive amount of carbon dioxide gas embolisms did not block the lungs, but rather directly entered the left heart through the foramen ovale, resulting in acute cerebral infarction. This consequence was difficult to diagnose, because invasive blood pressure monitoring during the procedure was very stable, there was no obvious circulatory abnormality or change of ETCO2, and only an unexpected transient fluctuation of the heart rate (45–120/min). According to the research literature, the reduction of ETCO2 is often the first sign of gas embolism, which generally decreases by more than 30%, and around half of patients will have some degree of cardiovascular event.[8] In this case, however, there was no obvious change in ETCO2. From the observation of vital signs, this was an occult cerebral infarction with gas embolisms, which is difficult to identify.
In our patient the final clinical outcome was favorable. In this paper, we show that the reason for the delayed recovery of patients identified in the PACU is not the residue of anesthetics, but rather cerebral infarction caused by carbon dioxide gas embolisms, which is extremely rare, manifested as lethal brainstem infarction. PFOs may be the underlying cause in about 40% of cryptogenic ischemic strokes reported in the literature.[10,11] We emphasize that the cause of postoperative coma may be cerebral infarction and paradoxical carbon dioxide gas embolism, in which a PFO is the pathogenesis. In this case, under the pneumoperitoneum pressure of 20 mm Hg, a large amount of carbon dioxide was absorbed into the circulation with the breach of the vena cava, entered the left heart through the potential PFO and was distributed to all organs. Diffuse gas embolisms blocked the endings of cerebral blood vessels, and the right brain injury was more serious as the patient was lying in left lateral decubitus position. It was in fact a case of whole-brain diffuse gas embolisms, although it was manifested as brainstem infarction. The patient gradually returned to normal 10 days after the operation, indicating that the prognosis was relatively good after the absorption of the carbon dioxide gas embolisms, and no obvious sequelae remained. It is reported that PFOs exist in about 25% to 35% of adults,[12] so once there is a vein rupture or break in this kind of patient, there will be a large amount of carbon dioxide gas absorbed into the circulation under a certain level of pneumoperitoneum pressure, which will directly enter the left heart through the foramen ovale, damaging major organs such as the brain, while there is no manifestation of pulmonary embolism. It also seems to suggest that pneumoperitoneum surgery may lead to serious complications in case of a ruptured vein, as the presence of a PFO is difficult to identify (by echocardiography preoperatively, or even by bedside transthoracic ultrasound postoperatively).
It is necessary to discuss whether it is worth continuing pneumoperitoneum surgery after vascular rupture, as target organs, for example, heart, lungs, and brain may suffer various degrees of injury. From the serious consequences in this case, of course, pneumoperitoneum should be ceased. Pneumoperitoneum pressure may cause gas to flow back into the vena cava and right atrium from the small veins; and in this case, the vena cava injury also increased the level of risk. But if there is vascular injury, must there necessarily be a switch to laparotomy? It has been reported that laparoscopic suturing of blood vessels as soon as possible can minimize the harm caused by air embolism, and it is not necessary to switch to laparotomy,[13] but the advantages and disadvantages need to be weighed. This case of cerebral infarction with gas embolism is occult, so it suggests that it is very important for a rapid diagnosis in this kind of situation. We think it is necessary to monitor transoesophageal echocardiography during this kind of surgery. If routine monitoring cannot be realized, at least pneumoperitoneum should be stopped when this difficult situation occurs; at the same time, transoesophageal echocardiography (TEE) intervention must be rapid for the diagnosis. Once paradoxical gas embolism is detected, pneumoperitoneum should be stopped and a switch made to laparotomy in time for hemostasis to avoid serious life-threatening complications in the cardiovascular and cerebrovascular systems. If there is no serious gas embolism, surgery under pneumoperitoneum can continue to ensure patients get the best benefit-risk ratio by avoiding laparotomy. TEE is a gold standard method, which can detect small bubbles of 5 to 10 μm at a concentration of 0.02 mL/kg.[14] The routine application of TEE can provide an early diagnosis of gas embolism and prevent it from further developing into clinically significant cardiovascular and cerebrovascular events.[15] In any case, when more gas emboli are identified, pneumoperitoneum should be stopped and switched to laparotomy, and the patient placed in the Trendelenburg position to prevent further damage to brain cells.
For this patient, the most likely explanation for the paradoxical gas embolism is the presence of a PFO. In this case, a contrast-enhanced echocardiography of the right heart was performed, the results of which were consistent with the sonography of a PFO. Because we identified that there were bubbles entering the left heart after 3 cardiac cycles, while we did not detect the PFO in the preoperative and postoperative transthoracic ultrasounds in this case, it cannot be ruled out that the PFO would only have opened under pneumoperitoneum pressure.
Another mechanism may exist. The explanation is that when a large amount of carbon dioxide enters the circulation, it exceeds the filtering effect of the lungs,[16] overflows into the left heart circulation, and impacts the brain cells. There is a report in the literature of circulatory failure caused by paradoxical gas embolism in the case of hepatic vein rupture, although there is no right to left shunt, and TEE detected bubbles in the left heart.[17] Under normal circumstances, the small bubbles that reach the pulmonary circulation will diffuse to the alveoli and be exhaled, preventing the gas from entering the left heart. However, the pulmonary circulation has a filter threshold for gases; once this threshold is exceeded, microbubbles will bypass the pulmonary circulation and be detected in the left heart.[1] It is worth noting that CO2 is a relatively safe gas, for example, a small amount of CO2 bubbles’ entering has no clinical significance, unless it impacts important organs, for example, embolizing coronary or cerebrovascular arteries as in this case, causing not only cerebral infarction, but also causing cardiac biomarkers to rise.
4 Conclusions
As far as we know, this is the first case of cerebral infarction caused by diffuse paradoxical CO2 gas embolism identified due to severe delayed recovery after retroperitoneal laparoscopic nephrectomy. This kind of dangerous gas embolism leading to cerebral infarction can occur quietly while vital signs are stable. The relevant pathophysiological changes need to be further analyzed to find the best treatment. When encountering the situation of blood vessel injury or rupture, the decision whether to continue pneumoperitoneum or convert to open surgery for hemostasis needs to take into account the risk-benefit ratio of patients. Anesthesiologists and surgeons should be aware of the risk of hidden catastrophic complications and maintain timely communication during the perioperative period. The method of treatment will vary on an individual basis, depending on differences in patients’ anatomy, but at such junctures the advantages and disadvantages should be weighed promptly and decisively to avoid serious systematic complications.
Acknowledgments
The authors thank the National Natural Science Foundation of China (81500178) and the Hospital Medical Research Foundation of Peking University Third Hospital (NO. BYSY2016004) for the support. Thanks to Richard Lester from Peking University Health Sciences Center for help in editing and polishing the language of this paper.
Author contributions
M.X. analyzed and interpreted the patient data regarding treatment details and images. Y.Y. performed the data acquisition and literature review, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.
Conceptualization: Youxiu Yao, Mao Xu.
Data curation: Mao Xu.
Funding acquisition: Youxiu Yao, Mao Xu.
Investigation: Youxiu Yao.
Supervision: Mao Xu.
Writing – original draft: Youxiu Yao.
Writing – review & editing: Youxiu Yao, Mao Xu.
Abbreviations: CT = computed tomography, ETCO2 = end tidal carbon dioxide, PFO = patent foramen ovale, TEE = transoesophageal echocardiography.
How to cite this article: Yao Y, Xu M. Carbon dioxide: the cause of devastating stroke without hemodynamic compromise during laparoscopic nephrectomy with injury of the inferior vena cava: a case report. Medicine. 2021;100:8(e24892).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | MANNITOL | DrugsGivenReaction | CC BY | 33663119 | 19,174,734 | 2021-02-26 |
What is the weight of the patient? | Carbon dioxide: the cause of devastating stroke without hemodynamic compromise during laparoscopic nephrectomy with injury of the inferior vena cava: A case report.
BACKGROUND
Carbon dioxide pneumoperitoneum in laparoscopic surgery can bring about occult perioperative cerebral infarction, advancing our understanding of the causes of severe postoperative delayed recovery.
Here, we report the case of a 35-year-old woman who underwent a right renal tumor resection in our institution, during which a raised pneumoperitoneum pressure (from 15 to 20 mm Hg) was adopted by the surgeon to prevent errhysis and to help stop the bleeding. Despite an accidental minor tearing of the inferior vena cava, vital signs remained stable throughout the procedure, and no obvious abnormality was observed in either end tidal carbon dioxide values or blood gas analysis. However, the patient unexpectedly suffered delayed recovery after the operation, presenting incomplete left hemiplegia and a positive Babinski sign.
Perioperative stroke was diagnosed by anesthesiologists, after excluding the effects of anesthesia. Cerebral hemorrhage was excluded, as no obvious abnormality was found in the density of brain parenchyma in the emergency computed tomography examination, and a digital subtraction angiography showed no abnormal thrombosis. Further magnetic resonance diagnosis led us to consider diffuse gas embolisms to be the cause of this acute stroke; a right echocardiography revealed that a patent foramen ovale (PFO) may account for the global cerebral gas embolisms.
METHODS
The patient received neuroprotective drugs (Vinpocetine, Edaravone, and Xingnaojing, which are commonly used as a standard of care in China), antiplatelets and other symptomatic treatments, plus dexamethasone to relieve edema. A contrast-enhanced echocardiography of the right heart was performed, the results of which were consistent with the sonography of a PFO.
RESULTS
The patient was hospitalized for 14 days and eventually discharged after recovery. At the latest follow-up in August 2019, the patient recovered without residual neurological sequelae.
CONCLUSIONS
Our results emphasize the need for vigilance regarding adverse cardiovascular and neurological events caused by carbon dioxide gas embolisms when encountering the inadvertent situation of vessels rupturing. Timely monitoring of paradoxical gas embolism by transoesophageal echocardiography is necessary and can avert the risk of severe complications. Urgent consideration should be given to stopping pneumoperitoneum and switching to laparotomy for hemostasis so that the patient can obtain the best benefit-risk ratio.
1 Introduction
Laparoscopic tumor resection is becoming increasingly popular among patients and surgeons due to its minimal invasiveness, clear vision, and fast postoperative recovery. Carbon dioxide is generally used for pneumoperitoneum, which is safe because of its high solubility in the blood, and its tendency not to produce gas embolism. Only when a large amount of carbon dioxide enters the circulatory system will embolism occur, with a very low incidence of about 0.15%.[1] In the process of tumor separation, occasional small lacerations of blood vessels are inevitable, resulting in a blurred visual field due to oozing blood. At such moments, is it appropriate to use pneumoperitoneum pressure to stop the bleeding and to continue the operation via laparoscopy? According to research reports, the first response of surgeons is that a certain degree of pneumoperitoneum pressure can help stop the bleeding,[2–4] but this will in turn increase the incidence of gas embolism[5] and also increase the complexity of perioperative management. Under these circumstances, carbon dioxide will be absorbed into the blood at pneumoperitoneum pressure, which will not only cause subcutaneous emphysema and delayed recovery (carbon dioxide anesthesia), but also damage to important organs, for example, heart, lungs, and brain, and even occasionally pulmonary embolism or paradoxical gas embolism.[6] This kind of gas embolism complication is rare but usually fatal, with a high probability of cardiac arrest,[7] which is usually accompanied by hemodynamic instability, a sharp drop in blood pressure, and a decrease[8] in end tidal carbon dioxide (ETCO2) values. However, paradoxical gas embolism causing cerebral infarction in laparoscopic surgery may still occur without observable abnormalities in blood pressure, CO2, and blood gas analysis, which is even rarer; to date no relevant report exists of such a case. Here, we report a case of occult cerebral infarction during retroperitoneal laparoscopic renal tumor resection with a minor tearing of the inferior vena cava, which was only identified due to severe delayed recovery.
2 Case presentation
The report was approved by the ethics review board of Peking University Third Hospital and was CARE compliant. Informed consent for publication was obtained from the patient.
The patient, a 35-year-old female (height 165 cm, weight 64 kg), was admitted to hospital due to flank pain persisting for more than 1 month, and was diagnosed with right renal carcinoma. It was therefore proposed to perform a laparoscopic right renal tumor resection under general anesthesia. The patient's previous medical history includes appendectomy and ectopic pregnancy surgery, and penicillin allergy. She had no communicable diseases, for example, hepatitis, tuberculosis, malaria; no history of hypertension, diabetes, and cardiac or cerebrovascular diseases; and no episodes of mental illness, trauma, blood transfusions, or food allergies. All preoperative evaluation tests, including routine blood, routine coagulation function, liver and kidney function, Electrocardiogram (ECG) and chest radiograph, were unremarkable. General anesthesia was induced using sufentanil 30 μg, etomidate 12 mg, propofol 80 mg, and rocuronium 50 mg, monitoring pulse oxygen saturation, capnography, ECG and invasive arterial blood pressure, and was maintained using a mixture of O2 1 L/min, air 1 L/min, sevoflurane 1.5 to 2.0 vol %, and remifentanil 0.05 to 0.2 μg/kg/min. The left lateral decubitus position is employed to facilitate the surgery.
Thirty minutes after the beginning of the surgery, the pneumoperitoneum pressure was increased (15–20 mm Hg) to help stop bleeding. At this point, ETCO2 was 41 mm Hg. During the procedure, an accidental minor tearing of the inferior vena cava occurred. A gauze compression was used to stop the bleeding, and the rupture was sutured as quickly as possible. ETCO2 (41–47 mm Hg) and invasive blood pressure were stable (118–145/65–79 mm Hg) during the process, and there were no obvious abnormal observations, except for the heart rate, which had a period of fluctuation (range 45–120 times/min); but then returned to normal with no specific treatment. Arterial blood gas analysis: pH = 7.30, PaCO2 = 48 mm Hg, PaO2 = 455 mm Hg, K+ = 3.2 mmol/L, Ca2+ = 1.13 mmol/L, HCO3- = 21.1 mmol/L, Glucose = 4.2 mmol/L, Base Excess = −3.8 mmol/L, Hb = 125 g/L, SaO2 = 100%. Anesthesiologists provided potassium supplement, increased the respiration rate of mechanical ventilation, and continued to observe without any further treatment. Subsequently, all indicators were stable and the operation was successfully completed. The bleeding volume was 50 mL, the urine output and the total input volumes were 100 and 2600 mL, respectively.
The patient was admitted to the post anesthesia care unit (PACU) and resumed regular spontaneous breathing (tidal volume > 400 mL, respiratory rate 16 times/min), was deoxidized for 10 min (SpO2 > 95%), and was then extubated after an intravenous injection of atropine 0.5 mg+ neostigmine 1 mg. After extubation, the patient had stable vital signs and normal spontaneous breathing, but woke up only after 2 hours, gazing to the left. She was unable to communicate, with poor recovered consciousness and frequent vomiting. Blood gas analysis in PACU: pH = 7.37, PaCO2 = 38 mm Hg, PaO2 = 114 mm Hg, K+ = 3.5 mmol/L, Ca2+ = 1.16 mmol/L, HCO3- = 21.4 mmol/L, Glucose = 6.4 mmol/L, Base Excess = −3.4 mmol/L, Hb = 128 g/L, SaO2 = 98%. The patient was given 10 mg metoclopramide intravenously for nausea and vomiting. In terms of recovery of consciousness, the patient exhibited a frowning reflex on the right side of the face in response to the noxious stimuli, while the observed left facial movement was less, attracting the attention of the perioperative physician. The anesthesiologist believed that this was not an ordinary case of delayed awakening, and communicated with the urologist and asked the neurologist for an urgent consultation. The patient's left upper limb movement was poor, the left lower limb could not move, and the left Babinski sign was positive; thus, cerebral hemorrhage or infarction was suspected. Subsequently, a noncontrast head computed tomography (CT) in emergency was performed, with no obvious abnormality found in the brain parenchymal density (Fig. 1A), thus excluding cerebral hemorrhage. According to the signs and symptoms, acute cerebral infarction with intracranial artery occlusion was hypothesized. A further digital subtraction angiography was performed in the department of vascular intervention, to prepare for interventional catheter thrombectomy and thrombolysis. Unexpectedly, no clear embolism was identified in the whole cerebrovascular system (Fig. 1B). According to the signs and symptoms, the patient was initially diagnosed as acute life-threatening brain stem infarction and was transferred to intensive care unit, due to the possibility of sudden death because of compression in the medulla oblongata cardiovascular center during the peak period of cerebral edema after brain stem infarction. The patient was intubated again due to hypoxemia (SpO2 89%). CT re-examination on the second postoperative day revealed only that the density of brain parenchyma was less uniform than before, and a new patchy, low-density shadow was observed in the right basal ganglia and temporal occipital lobe (Fig. 1C). The patient did not show any improvement, despite receiving neuroprotective drugs (Vinpocetine, Edaravone, and Xingnaojing, which are commonly used as a standard of care in China), antiplatelets and other symptomatic treatments, for example, mannitol dehydration treatment to reduce intracranial pressure, sedation, anti-infection, plus dexamethasone to relieve edema at the same time. The patient subsequently awoke, with her left limb movement showing obvious signs of recovery, at which point the doctors decided to transfer her to another hospital for hyperbaric oxygen therapy.
Figure 1 The imaging examination. A, An emergency CT examination was performed. No obvious abnormality was found in the density of brain parenchyma. B, DSA angiography showed no obvious abnormality in the whole cerebral blood vessel network (the image is the angiography image of the right carotid system). C, CT was rechecked 2 days after surgery, and the density of brain parenchyma was found to be uneven. On the right side, new patchy and slightly low-density shadows are seen in the basal ganglia and temporal occipital lobe. On the 5th day postsurgery, MR showed multiple lesions in bilateral brain, cerebellum, and brainstem, more pronounced on the right side; DWI, Diffusion Weighted Imaging images showed multiple spot-like, patch-like, line-like, and nodule-like high signal shadows in the bilateral cerebrum (D), cerebellum (E), and brainstem (F), more pronounced on the right side. G, The echocardiography reexamined after the operation showed that the structure of the heart was basically normal, no signal of left to right shunt was detected in the middle of the atrial septum; no echo interruption was detected, the ventricular septum was continuous and complete, and there was no sign of patent ductus arteriosus. H, Contrast echocardiography of the right heart. 10 days after the operation, normal saline contrast agent (agitated saline mixed with air) was injected by left elbow vein, the images of the right atrium and right ventricle were sequentially completed. And a small amount of contrast signal (blue arrow) appeared in the left atrium and left ventricle after 3 cardiac cycles. I, The above process is repeated twice, with identical results: in the image, the mitral valve has opened, and a small amount of contrast signal has entered the left ventricle. DSA = digital subtraction angiography, DWI = diffusion weighted imaging, MR = magnetic resonance.
The patient recovered consciousness on the third postoperative day. She was able to move her right limb according to instructions; the left upper limb had less pain-stimulus activity, while the left lower limb had no obvious pain-stimulus activity. The left Babinski sign was still positive. To further clarify the cause, a subsequent brain MRI examination was carried out when the patient's vital signs were stable, which showed a diffuse macular shadow of the whole brain, with gas embolism the suspected cause (Fig. 1D–F). On the seventh day after surgery, the movement of left upper and lower limbs was obviously improved, muscle strength was grade 5, and the left positive Babinski sign had disappeared.
It is worth mentioning that at the time of cerebral infarction, the patient also suffered from myocardial ischemia injury. The postoperative biomarker N-terminal pro-brain natriuretic peptide, and myocardial injury markers troponin I and creatine kinase MB also increased, as shown in Table 1.
Table 1 Postoperative changes of myocardial biomarkers in the patient.
Cardiac biomarkers (reference range) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
NT-proBNP, pg/mL (12–133) 70 1060 2120 1350 339 238
TnI, ng/mL (0.01–0.023) 0.110 0.900 0.250 0.110 0.064 0.031
CK-MB, ng/mL (0.1–4.94) 10 40 2.80 <2.0 2.10 3.30
CK-MB = creatine kinase MB, NT-proBNP = N-terminal pro-brain natriuretic peptide, TnI = troponin I.
According to the images from the brain magnetic resonance examination, it was concluded that the cerebral infarction was caused by gas embolisms. To further determine the cause, transthoracic echocardiography was re-examined after the patient had recovered, and no obvious atrial septal defect, ventricular septal defect, or patent ductus arteriosus was identified (Fig. 1G). Following this, a right heart contrast-enhanced echocardiography was performed, the results of which were consistent with the sonographic findings (Fig. 1H, I) of a potential patent foramen ovale (PFO). The diagnosis was clear considering that the cerebral infarction was caused by gas embolisms passing through the PFO channel. The patient was hospitalized for 14 days and discharged after recovery. The patient was diagnosed as having right renal clear cell carcinoma according to the postoperative pathological report. At the latest follow-up in August 2019, the patient was in good health without obvious sequelae.
3 Discussion
According to the literature, cerebral infarction caused by air embolisms in the perioperative period is very rare.[9] Carbon dioxide embolization following vascular injury in minimally invasive endoscopic surgery is also a rare but often fatal complication,[8] generally accompanied by pulmonary embolism and cardiovascular collapse. If identified in time, the change will be made to open surgery. Successful rescue will not lead to further serious neurological complications. One widely described mechanism of gas embolism is venous embolic occlusion due to retrograde upward migration of gas bubbles; but the possibility is invalid, as the left lateral decubitus position was used for our patient, and the head position was not higher than the right atrium. In the initial CT images, there was no evidence of bubbles in the cerebral sinuses. We believe that PFO is the most likely way for the gas bubbles to enter the arterial system, which was later confirmed by a right heart contrast echocardiography. In this case, due to the potential PFO, a massive amount of carbon dioxide gas embolisms did not block the lungs, but rather directly entered the left heart through the foramen ovale, resulting in acute cerebral infarction. This consequence was difficult to diagnose, because invasive blood pressure monitoring during the procedure was very stable, there was no obvious circulatory abnormality or change of ETCO2, and only an unexpected transient fluctuation of the heart rate (45–120/min). According to the research literature, the reduction of ETCO2 is often the first sign of gas embolism, which generally decreases by more than 30%, and around half of patients will have some degree of cardiovascular event.[8] In this case, however, there was no obvious change in ETCO2. From the observation of vital signs, this was an occult cerebral infarction with gas embolisms, which is difficult to identify.
In our patient the final clinical outcome was favorable. In this paper, we show that the reason for the delayed recovery of patients identified in the PACU is not the residue of anesthetics, but rather cerebral infarction caused by carbon dioxide gas embolisms, which is extremely rare, manifested as lethal brainstem infarction. PFOs may be the underlying cause in about 40% of cryptogenic ischemic strokes reported in the literature.[10,11] We emphasize that the cause of postoperative coma may be cerebral infarction and paradoxical carbon dioxide gas embolism, in which a PFO is the pathogenesis. In this case, under the pneumoperitoneum pressure of 20 mm Hg, a large amount of carbon dioxide was absorbed into the circulation with the breach of the vena cava, entered the left heart through the potential PFO and was distributed to all organs. Diffuse gas embolisms blocked the endings of cerebral blood vessels, and the right brain injury was more serious as the patient was lying in left lateral decubitus position. It was in fact a case of whole-brain diffuse gas embolisms, although it was manifested as brainstem infarction. The patient gradually returned to normal 10 days after the operation, indicating that the prognosis was relatively good after the absorption of the carbon dioxide gas embolisms, and no obvious sequelae remained. It is reported that PFOs exist in about 25% to 35% of adults,[12] so once there is a vein rupture or break in this kind of patient, there will be a large amount of carbon dioxide gas absorbed into the circulation under a certain level of pneumoperitoneum pressure, which will directly enter the left heart through the foramen ovale, damaging major organs such as the brain, while there is no manifestation of pulmonary embolism. It also seems to suggest that pneumoperitoneum surgery may lead to serious complications in case of a ruptured vein, as the presence of a PFO is difficult to identify (by echocardiography preoperatively, or even by bedside transthoracic ultrasound postoperatively).
It is necessary to discuss whether it is worth continuing pneumoperitoneum surgery after vascular rupture, as target organs, for example, heart, lungs, and brain may suffer various degrees of injury. From the serious consequences in this case, of course, pneumoperitoneum should be ceased. Pneumoperitoneum pressure may cause gas to flow back into the vena cava and right atrium from the small veins; and in this case, the vena cava injury also increased the level of risk. But if there is vascular injury, must there necessarily be a switch to laparotomy? It has been reported that laparoscopic suturing of blood vessels as soon as possible can minimize the harm caused by air embolism, and it is not necessary to switch to laparotomy,[13] but the advantages and disadvantages need to be weighed. This case of cerebral infarction with gas embolism is occult, so it suggests that it is very important for a rapid diagnosis in this kind of situation. We think it is necessary to monitor transoesophageal echocardiography during this kind of surgery. If routine monitoring cannot be realized, at least pneumoperitoneum should be stopped when this difficult situation occurs; at the same time, transoesophageal echocardiography (TEE) intervention must be rapid for the diagnosis. Once paradoxical gas embolism is detected, pneumoperitoneum should be stopped and a switch made to laparotomy in time for hemostasis to avoid serious life-threatening complications in the cardiovascular and cerebrovascular systems. If there is no serious gas embolism, surgery under pneumoperitoneum can continue to ensure patients get the best benefit-risk ratio by avoiding laparotomy. TEE is a gold standard method, which can detect small bubbles of 5 to 10 μm at a concentration of 0.02 mL/kg.[14] The routine application of TEE can provide an early diagnosis of gas embolism and prevent it from further developing into clinically significant cardiovascular and cerebrovascular events.[15] In any case, when more gas emboli are identified, pneumoperitoneum should be stopped and switched to laparotomy, and the patient placed in the Trendelenburg position to prevent further damage to brain cells.
For this patient, the most likely explanation for the paradoxical gas embolism is the presence of a PFO. In this case, a contrast-enhanced echocardiography of the right heart was performed, the results of which were consistent with the sonography of a PFO. Because we identified that there were bubbles entering the left heart after 3 cardiac cycles, while we did not detect the PFO in the preoperative and postoperative transthoracic ultrasounds in this case, it cannot be ruled out that the PFO would only have opened under pneumoperitoneum pressure.
Another mechanism may exist. The explanation is that when a large amount of carbon dioxide enters the circulation, it exceeds the filtering effect of the lungs,[16] overflows into the left heart circulation, and impacts the brain cells. There is a report in the literature of circulatory failure caused by paradoxical gas embolism in the case of hepatic vein rupture, although there is no right to left shunt, and TEE detected bubbles in the left heart.[17] Under normal circumstances, the small bubbles that reach the pulmonary circulation will diffuse to the alveoli and be exhaled, preventing the gas from entering the left heart. However, the pulmonary circulation has a filter threshold for gases; once this threshold is exceeded, microbubbles will bypass the pulmonary circulation and be detected in the left heart.[1] It is worth noting that CO2 is a relatively safe gas, for example, a small amount of CO2 bubbles’ entering has no clinical significance, unless it impacts important organs, for example, embolizing coronary or cerebrovascular arteries as in this case, causing not only cerebral infarction, but also causing cardiac biomarkers to rise.
4 Conclusions
As far as we know, this is the first case of cerebral infarction caused by diffuse paradoxical CO2 gas embolism identified due to severe delayed recovery after retroperitoneal laparoscopic nephrectomy. This kind of dangerous gas embolism leading to cerebral infarction can occur quietly while vital signs are stable. The relevant pathophysiological changes need to be further analyzed to find the best treatment. When encountering the situation of blood vessel injury or rupture, the decision whether to continue pneumoperitoneum or convert to open surgery for hemostasis needs to take into account the risk-benefit ratio of patients. Anesthesiologists and surgeons should be aware of the risk of hidden catastrophic complications and maintain timely communication during the perioperative period. The method of treatment will vary on an individual basis, depending on differences in patients’ anatomy, but at such junctures the advantages and disadvantages should be weighed promptly and decisively to avoid serious systematic complications.
Acknowledgments
The authors thank the National Natural Science Foundation of China (81500178) and the Hospital Medical Research Foundation of Peking University Third Hospital (NO. BYSY2016004) for the support. Thanks to Richard Lester from Peking University Health Sciences Center for help in editing and polishing the language of this paper.
Author contributions
M.X. analyzed and interpreted the patient data regarding treatment details and images. Y.Y. performed the data acquisition and literature review, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.
Conceptualization: Youxiu Yao, Mao Xu.
Data curation: Mao Xu.
Funding acquisition: Youxiu Yao, Mao Xu.
Investigation: Youxiu Yao.
Supervision: Mao Xu.
Writing – original draft: Youxiu Yao.
Writing – review & editing: Youxiu Yao, Mao Xu.
Abbreviations: CT = computed tomography, ETCO2 = end tidal carbon dioxide, PFO = patent foramen ovale, TEE = transoesophageal echocardiography.
How to cite this article: Yao Y, Xu M. Carbon dioxide: the cause of devastating stroke without hemodynamic compromise during laparoscopic nephrectomy with injury of the inferior vena cava: a case report. Medicine. 2021;100:8(e24892).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | 64 kg. | Weight | CC BY | 33663119 | 19,174,734 | 2021-02-26 |
What was the outcome of reaction 'Drug ineffective'? | Carbon dioxide: the cause of devastating stroke without hemodynamic compromise during laparoscopic nephrectomy with injury of the inferior vena cava: A case report.
BACKGROUND
Carbon dioxide pneumoperitoneum in laparoscopic surgery can bring about occult perioperative cerebral infarction, advancing our understanding of the causes of severe postoperative delayed recovery.
Here, we report the case of a 35-year-old woman who underwent a right renal tumor resection in our institution, during which a raised pneumoperitoneum pressure (from 15 to 20 mm Hg) was adopted by the surgeon to prevent errhysis and to help stop the bleeding. Despite an accidental minor tearing of the inferior vena cava, vital signs remained stable throughout the procedure, and no obvious abnormality was observed in either end tidal carbon dioxide values or blood gas analysis. However, the patient unexpectedly suffered delayed recovery after the operation, presenting incomplete left hemiplegia and a positive Babinski sign.
Perioperative stroke was diagnosed by anesthesiologists, after excluding the effects of anesthesia. Cerebral hemorrhage was excluded, as no obvious abnormality was found in the density of brain parenchyma in the emergency computed tomography examination, and a digital subtraction angiography showed no abnormal thrombosis. Further magnetic resonance diagnosis led us to consider diffuse gas embolisms to be the cause of this acute stroke; a right echocardiography revealed that a patent foramen ovale (PFO) may account for the global cerebral gas embolisms.
METHODS
The patient received neuroprotective drugs (Vinpocetine, Edaravone, and Xingnaojing, which are commonly used as a standard of care in China), antiplatelets and other symptomatic treatments, plus dexamethasone to relieve edema. A contrast-enhanced echocardiography of the right heart was performed, the results of which were consistent with the sonography of a PFO.
RESULTS
The patient was hospitalized for 14 days and eventually discharged after recovery. At the latest follow-up in August 2019, the patient recovered without residual neurological sequelae.
CONCLUSIONS
Our results emphasize the need for vigilance regarding adverse cardiovascular and neurological events caused by carbon dioxide gas embolisms when encountering the inadvertent situation of vessels rupturing. Timely monitoring of paradoxical gas embolism by transoesophageal echocardiography is necessary and can avert the risk of severe complications. Urgent consideration should be given to stopping pneumoperitoneum and switching to laparotomy for hemostasis so that the patient can obtain the best benefit-risk ratio.
1 Introduction
Laparoscopic tumor resection is becoming increasingly popular among patients and surgeons due to its minimal invasiveness, clear vision, and fast postoperative recovery. Carbon dioxide is generally used for pneumoperitoneum, which is safe because of its high solubility in the blood, and its tendency not to produce gas embolism. Only when a large amount of carbon dioxide enters the circulatory system will embolism occur, with a very low incidence of about 0.15%.[1] In the process of tumor separation, occasional small lacerations of blood vessels are inevitable, resulting in a blurred visual field due to oozing blood. At such moments, is it appropriate to use pneumoperitoneum pressure to stop the bleeding and to continue the operation via laparoscopy? According to research reports, the first response of surgeons is that a certain degree of pneumoperitoneum pressure can help stop the bleeding,[2–4] but this will in turn increase the incidence of gas embolism[5] and also increase the complexity of perioperative management. Under these circumstances, carbon dioxide will be absorbed into the blood at pneumoperitoneum pressure, which will not only cause subcutaneous emphysema and delayed recovery (carbon dioxide anesthesia), but also damage to important organs, for example, heart, lungs, and brain, and even occasionally pulmonary embolism or paradoxical gas embolism.[6] This kind of gas embolism complication is rare but usually fatal, with a high probability of cardiac arrest,[7] which is usually accompanied by hemodynamic instability, a sharp drop in blood pressure, and a decrease[8] in end tidal carbon dioxide (ETCO2) values. However, paradoxical gas embolism causing cerebral infarction in laparoscopic surgery may still occur without observable abnormalities in blood pressure, CO2, and blood gas analysis, which is even rarer; to date no relevant report exists of such a case. Here, we report a case of occult cerebral infarction during retroperitoneal laparoscopic renal tumor resection with a minor tearing of the inferior vena cava, which was only identified due to severe delayed recovery.
2 Case presentation
The report was approved by the ethics review board of Peking University Third Hospital and was CARE compliant. Informed consent for publication was obtained from the patient.
The patient, a 35-year-old female (height 165 cm, weight 64 kg), was admitted to hospital due to flank pain persisting for more than 1 month, and was diagnosed with right renal carcinoma. It was therefore proposed to perform a laparoscopic right renal tumor resection under general anesthesia. The patient's previous medical history includes appendectomy and ectopic pregnancy surgery, and penicillin allergy. She had no communicable diseases, for example, hepatitis, tuberculosis, malaria; no history of hypertension, diabetes, and cardiac or cerebrovascular diseases; and no episodes of mental illness, trauma, blood transfusions, or food allergies. All preoperative evaluation tests, including routine blood, routine coagulation function, liver and kidney function, Electrocardiogram (ECG) and chest radiograph, were unremarkable. General anesthesia was induced using sufentanil 30 μg, etomidate 12 mg, propofol 80 mg, and rocuronium 50 mg, monitoring pulse oxygen saturation, capnography, ECG and invasive arterial blood pressure, and was maintained using a mixture of O2 1 L/min, air 1 L/min, sevoflurane 1.5 to 2.0 vol %, and remifentanil 0.05 to 0.2 μg/kg/min. The left lateral decubitus position is employed to facilitate the surgery.
Thirty minutes after the beginning of the surgery, the pneumoperitoneum pressure was increased (15–20 mm Hg) to help stop bleeding. At this point, ETCO2 was 41 mm Hg. During the procedure, an accidental minor tearing of the inferior vena cava occurred. A gauze compression was used to stop the bleeding, and the rupture was sutured as quickly as possible. ETCO2 (41–47 mm Hg) and invasive blood pressure were stable (118–145/65–79 mm Hg) during the process, and there were no obvious abnormal observations, except for the heart rate, which had a period of fluctuation (range 45–120 times/min); but then returned to normal with no specific treatment. Arterial blood gas analysis: pH = 7.30, PaCO2 = 48 mm Hg, PaO2 = 455 mm Hg, K+ = 3.2 mmol/L, Ca2+ = 1.13 mmol/L, HCO3- = 21.1 mmol/L, Glucose = 4.2 mmol/L, Base Excess = −3.8 mmol/L, Hb = 125 g/L, SaO2 = 100%. Anesthesiologists provided potassium supplement, increased the respiration rate of mechanical ventilation, and continued to observe without any further treatment. Subsequently, all indicators were stable and the operation was successfully completed. The bleeding volume was 50 mL, the urine output and the total input volumes were 100 and 2600 mL, respectively.
The patient was admitted to the post anesthesia care unit (PACU) and resumed regular spontaneous breathing (tidal volume > 400 mL, respiratory rate 16 times/min), was deoxidized for 10 min (SpO2 > 95%), and was then extubated after an intravenous injection of atropine 0.5 mg+ neostigmine 1 mg. After extubation, the patient had stable vital signs and normal spontaneous breathing, but woke up only after 2 hours, gazing to the left. She was unable to communicate, with poor recovered consciousness and frequent vomiting. Blood gas analysis in PACU: pH = 7.37, PaCO2 = 38 mm Hg, PaO2 = 114 mm Hg, K+ = 3.5 mmol/L, Ca2+ = 1.16 mmol/L, HCO3- = 21.4 mmol/L, Glucose = 6.4 mmol/L, Base Excess = −3.4 mmol/L, Hb = 128 g/L, SaO2 = 98%. The patient was given 10 mg metoclopramide intravenously for nausea and vomiting. In terms of recovery of consciousness, the patient exhibited a frowning reflex on the right side of the face in response to the noxious stimuli, while the observed left facial movement was less, attracting the attention of the perioperative physician. The anesthesiologist believed that this was not an ordinary case of delayed awakening, and communicated with the urologist and asked the neurologist for an urgent consultation. The patient's left upper limb movement was poor, the left lower limb could not move, and the left Babinski sign was positive; thus, cerebral hemorrhage or infarction was suspected. Subsequently, a noncontrast head computed tomography (CT) in emergency was performed, with no obvious abnormality found in the brain parenchymal density (Fig. 1A), thus excluding cerebral hemorrhage. According to the signs and symptoms, acute cerebral infarction with intracranial artery occlusion was hypothesized. A further digital subtraction angiography was performed in the department of vascular intervention, to prepare for interventional catheter thrombectomy and thrombolysis. Unexpectedly, no clear embolism was identified in the whole cerebrovascular system (Fig. 1B). According to the signs and symptoms, the patient was initially diagnosed as acute life-threatening brain stem infarction and was transferred to intensive care unit, due to the possibility of sudden death because of compression in the medulla oblongata cardiovascular center during the peak period of cerebral edema after brain stem infarction. The patient was intubated again due to hypoxemia (SpO2 89%). CT re-examination on the second postoperative day revealed only that the density of brain parenchyma was less uniform than before, and a new patchy, low-density shadow was observed in the right basal ganglia and temporal occipital lobe (Fig. 1C). The patient did not show any improvement, despite receiving neuroprotective drugs (Vinpocetine, Edaravone, and Xingnaojing, which are commonly used as a standard of care in China), antiplatelets and other symptomatic treatments, for example, mannitol dehydration treatment to reduce intracranial pressure, sedation, anti-infection, plus dexamethasone to relieve edema at the same time. The patient subsequently awoke, with her left limb movement showing obvious signs of recovery, at which point the doctors decided to transfer her to another hospital for hyperbaric oxygen therapy.
Figure 1 The imaging examination. A, An emergency CT examination was performed. No obvious abnormality was found in the density of brain parenchyma. B, DSA angiography showed no obvious abnormality in the whole cerebral blood vessel network (the image is the angiography image of the right carotid system). C, CT was rechecked 2 days after surgery, and the density of brain parenchyma was found to be uneven. On the right side, new patchy and slightly low-density shadows are seen in the basal ganglia and temporal occipital lobe. On the 5th day postsurgery, MR showed multiple lesions in bilateral brain, cerebellum, and brainstem, more pronounced on the right side; DWI, Diffusion Weighted Imaging images showed multiple spot-like, patch-like, line-like, and nodule-like high signal shadows in the bilateral cerebrum (D), cerebellum (E), and brainstem (F), more pronounced on the right side. G, The echocardiography reexamined after the operation showed that the structure of the heart was basically normal, no signal of left to right shunt was detected in the middle of the atrial septum; no echo interruption was detected, the ventricular septum was continuous and complete, and there was no sign of patent ductus arteriosus. H, Contrast echocardiography of the right heart. 10 days after the operation, normal saline contrast agent (agitated saline mixed with air) was injected by left elbow vein, the images of the right atrium and right ventricle were sequentially completed. And a small amount of contrast signal (blue arrow) appeared in the left atrium and left ventricle after 3 cardiac cycles. I, The above process is repeated twice, with identical results: in the image, the mitral valve has opened, and a small amount of contrast signal has entered the left ventricle. DSA = digital subtraction angiography, DWI = diffusion weighted imaging, MR = magnetic resonance.
The patient recovered consciousness on the third postoperative day. She was able to move her right limb according to instructions; the left upper limb had less pain-stimulus activity, while the left lower limb had no obvious pain-stimulus activity. The left Babinski sign was still positive. To further clarify the cause, a subsequent brain MRI examination was carried out when the patient's vital signs were stable, which showed a diffuse macular shadow of the whole brain, with gas embolism the suspected cause (Fig. 1D–F). On the seventh day after surgery, the movement of left upper and lower limbs was obviously improved, muscle strength was grade 5, and the left positive Babinski sign had disappeared.
It is worth mentioning that at the time of cerebral infarction, the patient also suffered from myocardial ischemia injury. The postoperative biomarker N-terminal pro-brain natriuretic peptide, and myocardial injury markers troponin I and creatine kinase MB also increased, as shown in Table 1.
Table 1 Postoperative changes of myocardial biomarkers in the patient.
Cardiac biomarkers (reference range) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
NT-proBNP, pg/mL (12–133) 70 1060 2120 1350 339 238
TnI, ng/mL (0.01–0.023) 0.110 0.900 0.250 0.110 0.064 0.031
CK-MB, ng/mL (0.1–4.94) 10 40 2.80 <2.0 2.10 3.30
CK-MB = creatine kinase MB, NT-proBNP = N-terminal pro-brain natriuretic peptide, TnI = troponin I.
According to the images from the brain magnetic resonance examination, it was concluded that the cerebral infarction was caused by gas embolisms. To further determine the cause, transthoracic echocardiography was re-examined after the patient had recovered, and no obvious atrial septal defect, ventricular septal defect, or patent ductus arteriosus was identified (Fig. 1G). Following this, a right heart contrast-enhanced echocardiography was performed, the results of which were consistent with the sonographic findings (Fig. 1H, I) of a potential patent foramen ovale (PFO). The diagnosis was clear considering that the cerebral infarction was caused by gas embolisms passing through the PFO channel. The patient was hospitalized for 14 days and discharged after recovery. The patient was diagnosed as having right renal clear cell carcinoma according to the postoperative pathological report. At the latest follow-up in August 2019, the patient was in good health without obvious sequelae.
3 Discussion
According to the literature, cerebral infarction caused by air embolisms in the perioperative period is very rare.[9] Carbon dioxide embolization following vascular injury in minimally invasive endoscopic surgery is also a rare but often fatal complication,[8] generally accompanied by pulmonary embolism and cardiovascular collapse. If identified in time, the change will be made to open surgery. Successful rescue will not lead to further serious neurological complications. One widely described mechanism of gas embolism is venous embolic occlusion due to retrograde upward migration of gas bubbles; but the possibility is invalid, as the left lateral decubitus position was used for our patient, and the head position was not higher than the right atrium. In the initial CT images, there was no evidence of bubbles in the cerebral sinuses. We believe that PFO is the most likely way for the gas bubbles to enter the arterial system, which was later confirmed by a right heart contrast echocardiography. In this case, due to the potential PFO, a massive amount of carbon dioxide gas embolisms did not block the lungs, but rather directly entered the left heart through the foramen ovale, resulting in acute cerebral infarction. This consequence was difficult to diagnose, because invasive blood pressure monitoring during the procedure was very stable, there was no obvious circulatory abnormality or change of ETCO2, and only an unexpected transient fluctuation of the heart rate (45–120/min). According to the research literature, the reduction of ETCO2 is often the first sign of gas embolism, which generally decreases by more than 30%, and around half of patients will have some degree of cardiovascular event.[8] In this case, however, there was no obvious change in ETCO2. From the observation of vital signs, this was an occult cerebral infarction with gas embolisms, which is difficult to identify.
In our patient the final clinical outcome was favorable. In this paper, we show that the reason for the delayed recovery of patients identified in the PACU is not the residue of anesthetics, but rather cerebral infarction caused by carbon dioxide gas embolisms, which is extremely rare, manifested as lethal brainstem infarction. PFOs may be the underlying cause in about 40% of cryptogenic ischemic strokes reported in the literature.[10,11] We emphasize that the cause of postoperative coma may be cerebral infarction and paradoxical carbon dioxide gas embolism, in which a PFO is the pathogenesis. In this case, under the pneumoperitoneum pressure of 20 mm Hg, a large amount of carbon dioxide was absorbed into the circulation with the breach of the vena cava, entered the left heart through the potential PFO and was distributed to all organs. Diffuse gas embolisms blocked the endings of cerebral blood vessels, and the right brain injury was more serious as the patient was lying in left lateral decubitus position. It was in fact a case of whole-brain diffuse gas embolisms, although it was manifested as brainstem infarction. The patient gradually returned to normal 10 days after the operation, indicating that the prognosis was relatively good after the absorption of the carbon dioxide gas embolisms, and no obvious sequelae remained. It is reported that PFOs exist in about 25% to 35% of adults,[12] so once there is a vein rupture or break in this kind of patient, there will be a large amount of carbon dioxide gas absorbed into the circulation under a certain level of pneumoperitoneum pressure, which will directly enter the left heart through the foramen ovale, damaging major organs such as the brain, while there is no manifestation of pulmonary embolism. It also seems to suggest that pneumoperitoneum surgery may lead to serious complications in case of a ruptured vein, as the presence of a PFO is difficult to identify (by echocardiography preoperatively, or even by bedside transthoracic ultrasound postoperatively).
It is necessary to discuss whether it is worth continuing pneumoperitoneum surgery after vascular rupture, as target organs, for example, heart, lungs, and brain may suffer various degrees of injury. From the serious consequences in this case, of course, pneumoperitoneum should be ceased. Pneumoperitoneum pressure may cause gas to flow back into the vena cava and right atrium from the small veins; and in this case, the vena cava injury also increased the level of risk. But if there is vascular injury, must there necessarily be a switch to laparotomy? It has been reported that laparoscopic suturing of blood vessels as soon as possible can minimize the harm caused by air embolism, and it is not necessary to switch to laparotomy,[13] but the advantages and disadvantages need to be weighed. This case of cerebral infarction with gas embolism is occult, so it suggests that it is very important for a rapid diagnosis in this kind of situation. We think it is necessary to monitor transoesophageal echocardiography during this kind of surgery. If routine monitoring cannot be realized, at least pneumoperitoneum should be stopped when this difficult situation occurs; at the same time, transoesophageal echocardiography (TEE) intervention must be rapid for the diagnosis. Once paradoxical gas embolism is detected, pneumoperitoneum should be stopped and a switch made to laparotomy in time for hemostasis to avoid serious life-threatening complications in the cardiovascular and cerebrovascular systems. If there is no serious gas embolism, surgery under pneumoperitoneum can continue to ensure patients get the best benefit-risk ratio by avoiding laparotomy. TEE is a gold standard method, which can detect small bubbles of 5 to 10 μm at a concentration of 0.02 mL/kg.[14] The routine application of TEE can provide an early diagnosis of gas embolism and prevent it from further developing into clinically significant cardiovascular and cerebrovascular events.[15] In any case, when more gas emboli are identified, pneumoperitoneum should be stopped and switched to laparotomy, and the patient placed in the Trendelenburg position to prevent further damage to brain cells.
For this patient, the most likely explanation for the paradoxical gas embolism is the presence of a PFO. In this case, a contrast-enhanced echocardiography of the right heart was performed, the results of which were consistent with the sonography of a PFO. Because we identified that there were bubbles entering the left heart after 3 cardiac cycles, while we did not detect the PFO in the preoperative and postoperative transthoracic ultrasounds in this case, it cannot be ruled out that the PFO would only have opened under pneumoperitoneum pressure.
Another mechanism may exist. The explanation is that when a large amount of carbon dioxide enters the circulation, it exceeds the filtering effect of the lungs,[16] overflows into the left heart circulation, and impacts the brain cells. There is a report in the literature of circulatory failure caused by paradoxical gas embolism in the case of hepatic vein rupture, although there is no right to left shunt, and TEE detected bubbles in the left heart.[17] Under normal circumstances, the small bubbles that reach the pulmonary circulation will diffuse to the alveoli and be exhaled, preventing the gas from entering the left heart. However, the pulmonary circulation has a filter threshold for gases; once this threshold is exceeded, microbubbles will bypass the pulmonary circulation and be detected in the left heart.[1] It is worth noting that CO2 is a relatively safe gas, for example, a small amount of CO2 bubbles’ entering has no clinical significance, unless it impacts important organs, for example, embolizing coronary or cerebrovascular arteries as in this case, causing not only cerebral infarction, but also causing cardiac biomarkers to rise.
4 Conclusions
As far as we know, this is the first case of cerebral infarction caused by diffuse paradoxical CO2 gas embolism identified due to severe delayed recovery after retroperitoneal laparoscopic nephrectomy. This kind of dangerous gas embolism leading to cerebral infarction can occur quietly while vital signs are stable. The relevant pathophysiological changes need to be further analyzed to find the best treatment. When encountering the situation of blood vessel injury or rupture, the decision whether to continue pneumoperitoneum or convert to open surgery for hemostasis needs to take into account the risk-benefit ratio of patients. Anesthesiologists and surgeons should be aware of the risk of hidden catastrophic complications and maintain timely communication during the perioperative period. The method of treatment will vary on an individual basis, depending on differences in patients’ anatomy, but at such junctures the advantages and disadvantages should be weighed promptly and decisively to avoid serious systematic complications.
Acknowledgments
The authors thank the National Natural Science Foundation of China (81500178) and the Hospital Medical Research Foundation of Peking University Third Hospital (NO. BYSY2016004) for the support. Thanks to Richard Lester from Peking University Health Sciences Center for help in editing and polishing the language of this paper.
Author contributions
M.X. analyzed and interpreted the patient data regarding treatment details and images. Y.Y. performed the data acquisition and literature review, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.
Conceptualization: Youxiu Yao, Mao Xu.
Data curation: Mao Xu.
Funding acquisition: Youxiu Yao, Mao Xu.
Investigation: Youxiu Yao.
Supervision: Mao Xu.
Writing – original draft: Youxiu Yao.
Writing – review & editing: Youxiu Yao, Mao Xu.
Abbreviations: CT = computed tomography, ETCO2 = end tidal carbon dioxide, PFO = patent foramen ovale, TEE = transoesophageal echocardiography.
How to cite this article: Yao Y, Xu M. Carbon dioxide: the cause of devastating stroke without hemodynamic compromise during laparoscopic nephrectomy with injury of the inferior vena cava: a case report. Medicine. 2021;100:8(e24892).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | Recovered | ReactionOutcome | CC BY | 33663119 | 19,174,734 | 2021-02-26 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Management of idiopathic granulomatous mastitis in lactation: case report and review of the literature.
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition that mimics two common breast disorders: breast carcinoma and breast abscess. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and can significantly impact lactation. Despite the prevalence of this disease, no current literature describes an approach to managing IGM during breastfeeding.
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with worsening left breast swelling and redness. She underwent a mammogram, ultrasound and core needle biopsy that confirmed the diagnosis of Idiopathic Granulomatous Mastitis. During the postpartum period, she underwent intralesional triamcinolone injections of her left breast. Due to the contraindication of breastfeeding after local steroid injection, the patient stopped breastfeeding from the affected breast and continued breastfeeding unilaterally.
Idiopathic Granulomatous Mastitis is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Treatment of IGM during pregnancy and lactation has thus far not been addressed. We review the literature on the treatment of IGM in the non-lactating population, and propose considerations for treating breastfeeding women affected by this disease. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the following: side effects of systemic steroids, the need to wean a breast being treated with intralesional steroids, and augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Background
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition, first described in 1972 by Kessler and Wooloch, that mimics two common breast disorders: breast carcinoma and breast abscess [1]. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) and inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and is most common in women of Hispanic, Asian, Middle Eastern or African origin [2, 3]. Evaluation involves breast imaging with ultrasound and mammogram, and core needle biopsy to establish a diagnosis [4].
In the past, treatment of IGM involved incision and drainage of fluid collections, extensive debridement, mastectomy, as well as oral steroids, methotrexate and other anti-inflammatories including colchicine [5–7]. More recent management has shifted to minimally invasive approaches, including aspiration of fluid and intralesional injection of steroids [8, 9]. Additionally, methotrexate and azathioprine can be used as steroid-sparing agents and help promote long-term remission [10].
There is no consensus in the field regarding optimal management, even in non-lactating patients. Some of the uncertainty in treatment might come from uncertainty in causation. IGM has been thought of as infectious, inflammatory and autoimmune [11]. Recently, a few studies using low dose prednisone, 25 mg/day and 0.8 mg/kg/day have been shown effective in treatment of disease, supporting a more inflammatory or autoimmune etiology [12–14]. There is some suggestion that Corynebacterium kroppenstedtii is associated with IGM; however, there is no evidence that targeting these bacteria alters the disease course and may reflect normal breast microbiome [15, 16].
Treatment during breastfeeding poses a particular challenge in terms of managing symptoms and protecting lactation, though no current literature describes the approach to this clinical scenario. We describe the experience of a patient diagnosed during pregnancy with IGM, and her management during lactation. We review the literature on the treatment of IGM in the non-lactating population, and propose guidelines for treating breastfeeding women affected by this disease.
Case presentation
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with several months of left breast swelling and redness. At the recommendation of her obstetrician, she underwent diagnostic mammogram and ultrasound showing an ill-defined hypoechoic mass-like area in the left breast 10:00 position, 4 cm from the nipple. Core needle biopsy demonstrated granulomatous mastitis. She also had developed erythema nodosum on her bilateral lower extremities during pregnancy. Tuberculosis was ruled out. Evaluation for autoimmune disease, including serology, was negative. Her obstetrician started a steroid taper at 30 mg per day for a 6 day course, decreasing by 5 mg per day. The patient experienced improvement in pain and swelling during this time. This taper concluded 3 weeks prior to delivery; no further steroids were prescribed in order prevent hematologic or infectious complications at birth.
The patient began breastfeeding after delivery and continued to breastfeed from both breasts. She was not able to utilize an electric pump to express milk from her left breast due to discomfort and minimal milk extraction. She did report that the baby latched comfortably with audible swallows from the left breast, but she felt there was less milk production than from the right breast. The patient also felt she produced less milk in comparison to previously breastfeeding her other two children for 1 year without requiring infant formula. Beginning at 2 weeks postpartum, at the recommendation of the pediatrician, the patient initiated infant formula to maintain appropriate weight gain in the current infant. The infant had regained birthweight at two and a half weeks post- partum. Due to her left breast pain and swelling, the patient also restarted prednisone at 20 mg by mouth daily at 2 weeks postpartum.
She presented at 4 weeks postpartum to the breast surgeon for evaluation of worsening redness and pain in the left breast despite being compliant with prednisone. She noticed increased difficulty with her infant’s latch on the affected breast due to pain, as well as decreased swallows that she felt corresponded to decreased breastmilk volume. On exam, a large mass-like area with erythema and induration in the left breast was appreciated. This extended from the 9:00 to 4:00 position in the periareolar region, measuring approximately 8.0 × 8.0 × 9.0 cm total size. There was no fistula present.
The patient elected to undergo tapered discontinuation of her oral steroid over the course of 1 week and injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine into the affected areas of her left breast. Due to long-acting depot mechanism and high transfer of triamcinolone into breastmilk, the breast surgeon advised her to discontinue breastfeeding from the affected breast; triamcinolone was expected to remain in the breast for 3 weeks until the time of the next injection [17]. She initiated pumping on the unaffected right breast to stimulate increased production and continued to provide the infant with additional formula supplementation as needed. At the advice of her breast surgeon, she started galactagogues with brewer’s yeast and moringa three times daily. She used ibuprofen and acetaminophen as needed for pain, as well as warm compresses and ice. Her milk production on the left breast was low, and she did not require hand expression to relieve engorgement.
On follow up 3 weeks later, the patient had developed right nipple pain. This pain was considered related to increased engorgement in the right breast, as well as, the infant clamping in adjustment to increased flow of unilateral milk. The patient was instructed in lymphatic massage and utilized a laid-back breastfeeding position to reduce velocity of flow in the right breast [18, 19].
Her left breast pain had improved, and the mass had decreased in size to 6.0 × 6.0 × 5.0 cm from 11:00–3:00. She had developed a new draining fistula in the 1:00 position. An additional 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was injected into the affected areas of her left breast.
At 10 weeks postpartum (6 weeks after presentation to the breast surgeon), the patient indicated that she would like to attempt to resume breastfeeding from the affected left breast. On examination, the fistula was closed and there was a decreased mass-like area in the left breast to approximately 4.0 × 3.0 × 2.0 cm size. Therefore, no steroid injection was performed. The images showing the difference in volume between her right and left breasts at this time is demonstrated in Fig. 1. Comparison images demonstrating improvement in her left breast are illustrated in Fig. 2. Fig. 1 At 10 weeks postpartum, the left breast affected by IGM is no longer lactating; right breast is lactating
Fig. 2 a Left breast affected by IGM at week 3 after presentation (7 weeks postpartum) and (a) Left breast affected by IGM at week 6 after presentation (10 weeks postpartum)
Three weeks later, the patient presented with increased redness and pain in the previously affected left breast. The patient had attempted breastfeeding from the left breast, but had stopped due to pain and low milk production. A new fistula in the 1:00 position and developed with new erythema and fluctuance in the 7:00 position with an associated new 2.0 × 2.0 × 1.0 cm mass-like area. An injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was performed into the 1:00 and 7:00 positions of the left breast and she was advised to stop breastfeeding from the left breast after the injection.
At three-week follow-up, the patient had developed a new 9:00 position fistula, but there was decreased mass-like effect and erythema in the remainder of the breast. She elected to resume breastfeeding from the left breast and start and oral prednisone taper over 6 days, 30 mg of prednisone per day, tapering to 5 mg per day. She noticed gradual decrease in erythema and fluctuance and no new fistulae. She continued to breastfeed from both breasts until 7 months postpartum. At this point, she stopped breastfeeding due to gradual decrease in milk production over time.
Discussion and conclusions
Presentation
In all patients, whether lactating or not, IGM is a challenging clinical scenario to manage, particularly since many women experience a protracted waxing and waning course of symptoms. Some patients may present with a mass alone that spontaneously regresses, whereas others demonstrate significant erythema, fluid collection formation, and recurrent fistulization from the onset of the disease [20].
Most symptomatology is localized to the periareolar region extending outward [21]. As one area of inflammation becomes more quiescent, new disease may present in a new quadrant of the breast [20]. Without any intervention, the IGM generally will resolve within a few years of presentation [22]. With systemic immunosuppression with methotrexate and/or azathioprine, the disease tends to subside earlier. However, patients may experience a flare months after apparent resolution [10, 23]. Importantly, azathioprine has a good safety profile in pregnancy and lactation [24].
Evaluation and diagnosis
All patients with suspected IGM require breast imaging and core needle biopsy to confirm diagnosis; this is safe in breastfeeding [2]. Tuberculosis should be ruled out [25] and patients should be referred to a rheumatologist to rule out underlying autoimmune disorder. The relationship with erythema nodosum and IGM is unclear, but it has been hypothesized that it can represent an extra-mammary form of IGM [26].
General principles of treatment
In the non-lactating population, traditional treatment has included systemic steroids, methotrexate and antibiotics, local care involves procedures ranging from incision and drainage, wide local excision with wound vacuum placement, or mastectomy [2, 27]. A systematic review of 3060 patients found that more industrialized countries use surgery more frequently, and more rural countries have a tendency to rely more heavily on antibiotics [28]. Regardless of location, steroids are often used, and it is common for IGM to require a combination of several therapies [28]. A large study of IGM that investigated 206 individuals in Iran recommends corticosteroids as first line treatment for this disease [3]. There are reports of surgical management with improved cosmetic outcomes and minimal complications, including mastectomy with immediate reconstruction, but there is also report of surgery causing increased inflammatory reaction and fistulazation [7, 10, 29]. While anti-tuberculosis agents such as rifampin have been utilized, they also have been associated with rebound inflammation [30, 31].
Cultures of fluid collections often demonstrate Corynebacterium, Streptococci, Staphylococci or Bacteroides; however, the traditionally utilized antibiotics of doxycycline and trimethoprim-sulfamethoxazole have not shown clinically significant results in terms of disease severity or duration [32, 33]. This is likely related to the thought that IGM is an inflammatory rather than infectious disease, and culture results reflect the presence of common breast flora [34]. More recently, IGM has been thought to have a significant autoimmune component, which supports the notion that localized steroids could be an effective treatment strategy [31].
Surgical intervention also remains controversial. While one study demonstrates a shortened duration to resolution compared with steroid injections and observation alone, not all cases require such aggressive treatment [9]. More recently, it has become clear that repeated surgical intervention can potentiate inflammation and can increase disease severity [35]. One group compared recurrence for individuals who were treated with antibiotics and wide local excision, or incision and drainage plus steroids. The less invasive approach had significantly less recurrence [35]. A retrospective study that demonstrated excision had a lower recurrence rate than the comparison group. However, this study was limited in that the comparison underwent warm compress, herb application, and drainage alone; this conservative approach without steroids would not be expected to treat the disease effectively [36].
Instead of traditional invasive approaches that have not demonstrated clear success, intralesional triamcinolone injections every 1–2 weeks represent a promising minimally invasive approach with limited systemic side effects and good outcomes [37]. After the first steroid injection, patients experience a marked decrease in disease volume, symptoms, and frequency of recurrence [37]. Additionally, patients who receive steroid injections were likely to achieve a complete recovery without the adverse effects of oral steroids [37]. The frequency of injection can be adapted based on clinical circumstances, such as severity of presentation.
While triamcinolone injection directly into breast lesions can relieve symptoms, due to the potential for infant exposure to the steroid via breast milk, this treatment modality is not compatible with continued breastfeeding on the treated breast(s). This is related to high oral dose to infant and the potential infant side effects of growth suppression, and interference with corticosteroid production [17]. The procedure for intralesional injection is outlined below, and can be performed with or without ultrasound guidance with an 18-gauge needle. Clean skin
Aspirate any existing fluid
Mix 40 mg/ 1 mL triamcinolone with 3 mL 2% lidocaine for a total volume of 4 mL
Inject deeply into areas of active fistula, mass, erythema or induration.
Wound care should consist of managing drainage from fistulae with gauze and other non-adherent dressings. Tape should be avoided due to further abrasion and irritation of skin. Patients often experience significant distress related to the symptoms of the disease and psychosocial support should be provided.
Treatment during lactation
There is no data to suggest that breastfeeding prolongs the duration of symptoms of IGM, and the diagnosis of IGM does not preclude lactation. Interestingly, a recent study demonstrated a small minority of IGM patients, not in the lactational period, who have demonstrated elevated prolactin from either dopamine antagonist medications or a prolactinoma [38]. Like much of other proposed pathophysiologic mechanisms in IGM, the exact relationship to prolactin remains unclear.
Special considerations for treatment for breastfeeding women include the fact that oral steroids decrease milk production [39]. Maternal insomnia, agitation, and risk for depression also are of concern in the postpartum population [39, 40]. Triamcinolone injections in the breast are contraindicated with breastfeeding from that breast for approximately 2 weeks [17]. In high doses such as those used with anti-neoplastic therapy, methotrexate is not compatible with breastfeeding. Limited information suggests that single or weekly doses may demonstrate low levels of methotrexate in breastmilk, but some expert opinions also warn against this use during lactation [41]. Azathioprine as studied primarily in inflammatory bowel disease populations, is safe during lactation, may provide more ideal systemic therapy in the breastfeeding population [42].
We recommend individualized care with considerations given to the following options: Continuing oral steroids with knowledge oral steroids may not be particularly effective. Systemic steroids cause known side effects as outlined above, including reduction in milk production, insomnia, agitation, and depression, however low-dose or even higher doses for a short duration are likely compatible with lactation [39].
Avoiding use of methotrexate, which is generally incompatible with lactation. Consideration of azathioprine, which is compatible with lactation.
Stopping breastfeeding and pumping from the affected breast, augmenting production on the unaffected breast, and utilizing intralesional triamcinolone injections on the affected breast.
Not utilizing steroids and managing patients with supportive care only, such as gauze for draining fistulae to keep skin dry and minimize maceration.
Pain management including non-steroidal anti-inflammatory medications such as ibuprofen and acetaminophen, as well as conservative management with ice and heat per patient comfort.
Repeated antibiotic treatments are not effective and can result in unintended and avoidable side effects, such as Clostridium difficile infections, gastrointestinal distress and future resistance.
Psychosocial support for patient distress and discomfort
Lactation consultant (IBCLC) involvement or other breastfeeding specialist to assist in unilateral weaning, to assure adequate milk supply and to offer breastfeeding support.
In conclusion, IGM is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the side effects of systemic steroids; the need to wean a breast being treated with intralesional steroids; and, augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Abbreviations
IGM Idiopathic Granulomatous Mastitis
NAC Nipple Areolar Complex
Acknowledgements
None.
Authors’ contributions
All authors wrote, read and approved the final manuscript. Dr. Katrina Mitchell took care of and treated the patient.
Funding
Not Applicable.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
This study was IRB Approved at the Presbyterian Hospital Albuquerque, New Mexico after direct consent was obtained from the patient.
Consent for publication
The patient is aware, and accepting, of her case being submitted for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACETAMINOPHEN, IBUPROFEN, LIDOCAINE, PREDNISOLONE, SACCHAROMYCES CEREVISIAE, TRIAMCINOLONE | DrugsGivenReaction | CC BY | 33663552 | 20,160,158 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Management of idiopathic granulomatous mastitis in lactation: case report and review of the literature.
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition that mimics two common breast disorders: breast carcinoma and breast abscess. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and can significantly impact lactation. Despite the prevalence of this disease, no current literature describes an approach to managing IGM during breastfeeding.
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with worsening left breast swelling and redness. She underwent a mammogram, ultrasound and core needle biopsy that confirmed the diagnosis of Idiopathic Granulomatous Mastitis. During the postpartum period, she underwent intralesional triamcinolone injections of her left breast. Due to the contraindication of breastfeeding after local steroid injection, the patient stopped breastfeeding from the affected breast and continued breastfeeding unilaterally.
Idiopathic Granulomatous Mastitis is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Treatment of IGM during pregnancy and lactation has thus far not been addressed. We review the literature on the treatment of IGM in the non-lactating population, and propose considerations for treating breastfeeding women affected by this disease. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the following: side effects of systemic steroids, the need to wean a breast being treated with intralesional steroids, and augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Background
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition, first described in 1972 by Kessler and Wooloch, that mimics two common breast disorders: breast carcinoma and breast abscess [1]. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) and inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and is most common in women of Hispanic, Asian, Middle Eastern or African origin [2, 3]. Evaluation involves breast imaging with ultrasound and mammogram, and core needle biopsy to establish a diagnosis [4].
In the past, treatment of IGM involved incision and drainage of fluid collections, extensive debridement, mastectomy, as well as oral steroids, methotrexate and other anti-inflammatories including colchicine [5–7]. More recent management has shifted to minimally invasive approaches, including aspiration of fluid and intralesional injection of steroids [8, 9]. Additionally, methotrexate and azathioprine can be used as steroid-sparing agents and help promote long-term remission [10].
There is no consensus in the field regarding optimal management, even in non-lactating patients. Some of the uncertainty in treatment might come from uncertainty in causation. IGM has been thought of as infectious, inflammatory and autoimmune [11]. Recently, a few studies using low dose prednisone, 25 mg/day and 0.8 mg/kg/day have been shown effective in treatment of disease, supporting a more inflammatory or autoimmune etiology [12–14]. There is some suggestion that Corynebacterium kroppenstedtii is associated with IGM; however, there is no evidence that targeting these bacteria alters the disease course and may reflect normal breast microbiome [15, 16].
Treatment during breastfeeding poses a particular challenge in terms of managing symptoms and protecting lactation, though no current literature describes the approach to this clinical scenario. We describe the experience of a patient diagnosed during pregnancy with IGM, and her management during lactation. We review the literature on the treatment of IGM in the non-lactating population, and propose guidelines for treating breastfeeding women affected by this disease.
Case presentation
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with several months of left breast swelling and redness. At the recommendation of her obstetrician, she underwent diagnostic mammogram and ultrasound showing an ill-defined hypoechoic mass-like area in the left breast 10:00 position, 4 cm from the nipple. Core needle biopsy demonstrated granulomatous mastitis. She also had developed erythema nodosum on her bilateral lower extremities during pregnancy. Tuberculosis was ruled out. Evaluation for autoimmune disease, including serology, was negative. Her obstetrician started a steroid taper at 30 mg per day for a 6 day course, decreasing by 5 mg per day. The patient experienced improvement in pain and swelling during this time. This taper concluded 3 weeks prior to delivery; no further steroids were prescribed in order prevent hematologic or infectious complications at birth.
The patient began breastfeeding after delivery and continued to breastfeed from both breasts. She was not able to utilize an electric pump to express milk from her left breast due to discomfort and minimal milk extraction. She did report that the baby latched comfortably with audible swallows from the left breast, but she felt there was less milk production than from the right breast. The patient also felt she produced less milk in comparison to previously breastfeeding her other two children for 1 year without requiring infant formula. Beginning at 2 weeks postpartum, at the recommendation of the pediatrician, the patient initiated infant formula to maintain appropriate weight gain in the current infant. The infant had regained birthweight at two and a half weeks post- partum. Due to her left breast pain and swelling, the patient also restarted prednisone at 20 mg by mouth daily at 2 weeks postpartum.
She presented at 4 weeks postpartum to the breast surgeon for evaluation of worsening redness and pain in the left breast despite being compliant with prednisone. She noticed increased difficulty with her infant’s latch on the affected breast due to pain, as well as decreased swallows that she felt corresponded to decreased breastmilk volume. On exam, a large mass-like area with erythema and induration in the left breast was appreciated. This extended from the 9:00 to 4:00 position in the periareolar region, measuring approximately 8.0 × 8.0 × 9.0 cm total size. There was no fistula present.
The patient elected to undergo tapered discontinuation of her oral steroid over the course of 1 week and injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine into the affected areas of her left breast. Due to long-acting depot mechanism and high transfer of triamcinolone into breastmilk, the breast surgeon advised her to discontinue breastfeeding from the affected breast; triamcinolone was expected to remain in the breast for 3 weeks until the time of the next injection [17]. She initiated pumping on the unaffected right breast to stimulate increased production and continued to provide the infant with additional formula supplementation as needed. At the advice of her breast surgeon, she started galactagogues with brewer’s yeast and moringa three times daily. She used ibuprofen and acetaminophen as needed for pain, as well as warm compresses and ice. Her milk production on the left breast was low, and she did not require hand expression to relieve engorgement.
On follow up 3 weeks later, the patient had developed right nipple pain. This pain was considered related to increased engorgement in the right breast, as well as, the infant clamping in adjustment to increased flow of unilateral milk. The patient was instructed in lymphatic massage and utilized a laid-back breastfeeding position to reduce velocity of flow in the right breast [18, 19].
Her left breast pain had improved, and the mass had decreased in size to 6.0 × 6.0 × 5.0 cm from 11:00–3:00. She had developed a new draining fistula in the 1:00 position. An additional 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was injected into the affected areas of her left breast.
At 10 weeks postpartum (6 weeks after presentation to the breast surgeon), the patient indicated that she would like to attempt to resume breastfeeding from the affected left breast. On examination, the fistula was closed and there was a decreased mass-like area in the left breast to approximately 4.0 × 3.0 × 2.0 cm size. Therefore, no steroid injection was performed. The images showing the difference in volume between her right and left breasts at this time is demonstrated in Fig. 1. Comparison images demonstrating improvement in her left breast are illustrated in Fig. 2. Fig. 1 At 10 weeks postpartum, the left breast affected by IGM is no longer lactating; right breast is lactating
Fig. 2 a Left breast affected by IGM at week 3 after presentation (7 weeks postpartum) and (a) Left breast affected by IGM at week 6 after presentation (10 weeks postpartum)
Three weeks later, the patient presented with increased redness and pain in the previously affected left breast. The patient had attempted breastfeeding from the left breast, but had stopped due to pain and low milk production. A new fistula in the 1:00 position and developed with new erythema and fluctuance in the 7:00 position with an associated new 2.0 × 2.0 × 1.0 cm mass-like area. An injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was performed into the 1:00 and 7:00 positions of the left breast and she was advised to stop breastfeeding from the left breast after the injection.
At three-week follow-up, the patient had developed a new 9:00 position fistula, but there was decreased mass-like effect and erythema in the remainder of the breast. She elected to resume breastfeeding from the left breast and start and oral prednisone taper over 6 days, 30 mg of prednisone per day, tapering to 5 mg per day. She noticed gradual decrease in erythema and fluctuance and no new fistulae. She continued to breastfeed from both breasts until 7 months postpartum. At this point, she stopped breastfeeding due to gradual decrease in milk production over time.
Discussion and conclusions
Presentation
In all patients, whether lactating or not, IGM is a challenging clinical scenario to manage, particularly since many women experience a protracted waxing and waning course of symptoms. Some patients may present with a mass alone that spontaneously regresses, whereas others demonstrate significant erythema, fluid collection formation, and recurrent fistulization from the onset of the disease [20].
Most symptomatology is localized to the periareolar region extending outward [21]. As one area of inflammation becomes more quiescent, new disease may present in a new quadrant of the breast [20]. Without any intervention, the IGM generally will resolve within a few years of presentation [22]. With systemic immunosuppression with methotrexate and/or azathioprine, the disease tends to subside earlier. However, patients may experience a flare months after apparent resolution [10, 23]. Importantly, azathioprine has a good safety profile in pregnancy and lactation [24].
Evaluation and diagnosis
All patients with suspected IGM require breast imaging and core needle biopsy to confirm diagnosis; this is safe in breastfeeding [2]. Tuberculosis should be ruled out [25] and patients should be referred to a rheumatologist to rule out underlying autoimmune disorder. The relationship with erythema nodosum and IGM is unclear, but it has been hypothesized that it can represent an extra-mammary form of IGM [26].
General principles of treatment
In the non-lactating population, traditional treatment has included systemic steroids, methotrexate and antibiotics, local care involves procedures ranging from incision and drainage, wide local excision with wound vacuum placement, or mastectomy [2, 27]. A systematic review of 3060 patients found that more industrialized countries use surgery more frequently, and more rural countries have a tendency to rely more heavily on antibiotics [28]. Regardless of location, steroids are often used, and it is common for IGM to require a combination of several therapies [28]. A large study of IGM that investigated 206 individuals in Iran recommends corticosteroids as first line treatment for this disease [3]. There are reports of surgical management with improved cosmetic outcomes and minimal complications, including mastectomy with immediate reconstruction, but there is also report of surgery causing increased inflammatory reaction and fistulazation [7, 10, 29]. While anti-tuberculosis agents such as rifampin have been utilized, they also have been associated with rebound inflammation [30, 31].
Cultures of fluid collections often demonstrate Corynebacterium, Streptococci, Staphylococci or Bacteroides; however, the traditionally utilized antibiotics of doxycycline and trimethoprim-sulfamethoxazole have not shown clinically significant results in terms of disease severity or duration [32, 33]. This is likely related to the thought that IGM is an inflammatory rather than infectious disease, and culture results reflect the presence of common breast flora [34]. More recently, IGM has been thought to have a significant autoimmune component, which supports the notion that localized steroids could be an effective treatment strategy [31].
Surgical intervention also remains controversial. While one study demonstrates a shortened duration to resolution compared with steroid injections and observation alone, not all cases require such aggressive treatment [9]. More recently, it has become clear that repeated surgical intervention can potentiate inflammation and can increase disease severity [35]. One group compared recurrence for individuals who were treated with antibiotics and wide local excision, or incision and drainage plus steroids. The less invasive approach had significantly less recurrence [35]. A retrospective study that demonstrated excision had a lower recurrence rate than the comparison group. However, this study was limited in that the comparison underwent warm compress, herb application, and drainage alone; this conservative approach without steroids would not be expected to treat the disease effectively [36].
Instead of traditional invasive approaches that have not demonstrated clear success, intralesional triamcinolone injections every 1–2 weeks represent a promising minimally invasive approach with limited systemic side effects and good outcomes [37]. After the first steroid injection, patients experience a marked decrease in disease volume, symptoms, and frequency of recurrence [37]. Additionally, patients who receive steroid injections were likely to achieve a complete recovery without the adverse effects of oral steroids [37]. The frequency of injection can be adapted based on clinical circumstances, such as severity of presentation.
While triamcinolone injection directly into breast lesions can relieve symptoms, due to the potential for infant exposure to the steroid via breast milk, this treatment modality is not compatible with continued breastfeeding on the treated breast(s). This is related to high oral dose to infant and the potential infant side effects of growth suppression, and interference with corticosteroid production [17]. The procedure for intralesional injection is outlined below, and can be performed with or without ultrasound guidance with an 18-gauge needle. Clean skin
Aspirate any existing fluid
Mix 40 mg/ 1 mL triamcinolone with 3 mL 2% lidocaine for a total volume of 4 mL
Inject deeply into areas of active fistula, mass, erythema or induration.
Wound care should consist of managing drainage from fistulae with gauze and other non-adherent dressings. Tape should be avoided due to further abrasion and irritation of skin. Patients often experience significant distress related to the symptoms of the disease and psychosocial support should be provided.
Treatment during lactation
There is no data to suggest that breastfeeding prolongs the duration of symptoms of IGM, and the diagnosis of IGM does not preclude lactation. Interestingly, a recent study demonstrated a small minority of IGM patients, not in the lactational period, who have demonstrated elevated prolactin from either dopamine antagonist medications or a prolactinoma [38]. Like much of other proposed pathophysiologic mechanisms in IGM, the exact relationship to prolactin remains unclear.
Special considerations for treatment for breastfeeding women include the fact that oral steroids decrease milk production [39]. Maternal insomnia, agitation, and risk for depression also are of concern in the postpartum population [39, 40]. Triamcinolone injections in the breast are contraindicated with breastfeeding from that breast for approximately 2 weeks [17]. In high doses such as those used with anti-neoplastic therapy, methotrexate is not compatible with breastfeeding. Limited information suggests that single or weekly doses may demonstrate low levels of methotrexate in breastmilk, but some expert opinions also warn against this use during lactation [41]. Azathioprine as studied primarily in inflammatory bowel disease populations, is safe during lactation, may provide more ideal systemic therapy in the breastfeeding population [42].
We recommend individualized care with considerations given to the following options: Continuing oral steroids with knowledge oral steroids may not be particularly effective. Systemic steroids cause known side effects as outlined above, including reduction in milk production, insomnia, agitation, and depression, however low-dose or even higher doses for a short duration are likely compatible with lactation [39].
Avoiding use of methotrexate, which is generally incompatible with lactation. Consideration of azathioprine, which is compatible with lactation.
Stopping breastfeeding and pumping from the affected breast, augmenting production on the unaffected breast, and utilizing intralesional triamcinolone injections on the affected breast.
Not utilizing steroids and managing patients with supportive care only, such as gauze for draining fistulae to keep skin dry and minimize maceration.
Pain management including non-steroidal anti-inflammatory medications such as ibuprofen and acetaminophen, as well as conservative management with ice and heat per patient comfort.
Repeated antibiotic treatments are not effective and can result in unintended and avoidable side effects, such as Clostridium difficile infections, gastrointestinal distress and future resistance.
Psychosocial support for patient distress and discomfort
Lactation consultant (IBCLC) involvement or other breastfeeding specialist to assist in unilateral weaning, to assure adequate milk supply and to offer breastfeeding support.
In conclusion, IGM is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the side effects of systemic steroids; the need to wean a breast being treated with intralesional steroids; and, augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Abbreviations
IGM Idiopathic Granulomatous Mastitis
NAC Nipple Areolar Complex
Acknowledgements
None.
Authors’ contributions
All authors wrote, read and approved the final manuscript. Dr. Katrina Mitchell took care of and treated the patient.
Funding
Not Applicable.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
This study was IRB Approved at the Presbyterian Hospital Albuquerque, New Mexico after direct consent was obtained from the patient.
Consent for publication
The patient is aware, and accepting, of her case being submitted for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACETAMINOPHEN, IBUPROFEN, LIDOCAINE, PREDNISOLONE, SACCHAROMYCES CEREVISIAE, TRIAMCINOLONE | DrugsGivenReaction | CC BY | 33663552 | 20,160,158 | 2021-03-04 |
What was the administration route of drug 'PREDNISOLONE'? | Management of idiopathic granulomatous mastitis in lactation: case report and review of the literature.
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition that mimics two common breast disorders: breast carcinoma and breast abscess. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and can significantly impact lactation. Despite the prevalence of this disease, no current literature describes an approach to managing IGM during breastfeeding.
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with worsening left breast swelling and redness. She underwent a mammogram, ultrasound and core needle biopsy that confirmed the diagnosis of Idiopathic Granulomatous Mastitis. During the postpartum period, she underwent intralesional triamcinolone injections of her left breast. Due to the contraindication of breastfeeding after local steroid injection, the patient stopped breastfeeding from the affected breast and continued breastfeeding unilaterally.
Idiopathic Granulomatous Mastitis is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Treatment of IGM during pregnancy and lactation has thus far not been addressed. We review the literature on the treatment of IGM in the non-lactating population, and propose considerations for treating breastfeeding women affected by this disease. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the following: side effects of systemic steroids, the need to wean a breast being treated with intralesional steroids, and augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Background
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition, first described in 1972 by Kessler and Wooloch, that mimics two common breast disorders: breast carcinoma and breast abscess [1]. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) and inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and is most common in women of Hispanic, Asian, Middle Eastern or African origin [2, 3]. Evaluation involves breast imaging with ultrasound and mammogram, and core needle biopsy to establish a diagnosis [4].
In the past, treatment of IGM involved incision and drainage of fluid collections, extensive debridement, mastectomy, as well as oral steroids, methotrexate and other anti-inflammatories including colchicine [5–7]. More recent management has shifted to minimally invasive approaches, including aspiration of fluid and intralesional injection of steroids [8, 9]. Additionally, methotrexate and azathioprine can be used as steroid-sparing agents and help promote long-term remission [10].
There is no consensus in the field regarding optimal management, even in non-lactating patients. Some of the uncertainty in treatment might come from uncertainty in causation. IGM has been thought of as infectious, inflammatory and autoimmune [11]. Recently, a few studies using low dose prednisone, 25 mg/day and 0.8 mg/kg/day have been shown effective in treatment of disease, supporting a more inflammatory or autoimmune etiology [12–14]. There is some suggestion that Corynebacterium kroppenstedtii is associated with IGM; however, there is no evidence that targeting these bacteria alters the disease course and may reflect normal breast microbiome [15, 16].
Treatment during breastfeeding poses a particular challenge in terms of managing symptoms and protecting lactation, though no current literature describes the approach to this clinical scenario. We describe the experience of a patient diagnosed during pregnancy with IGM, and her management during lactation. We review the literature on the treatment of IGM in the non-lactating population, and propose guidelines for treating breastfeeding women affected by this disease.
Case presentation
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with several months of left breast swelling and redness. At the recommendation of her obstetrician, she underwent diagnostic mammogram and ultrasound showing an ill-defined hypoechoic mass-like area in the left breast 10:00 position, 4 cm from the nipple. Core needle biopsy demonstrated granulomatous mastitis. She also had developed erythema nodosum on her bilateral lower extremities during pregnancy. Tuberculosis was ruled out. Evaluation for autoimmune disease, including serology, was negative. Her obstetrician started a steroid taper at 30 mg per day for a 6 day course, decreasing by 5 mg per day. The patient experienced improvement in pain and swelling during this time. This taper concluded 3 weeks prior to delivery; no further steroids were prescribed in order prevent hematologic or infectious complications at birth.
The patient began breastfeeding after delivery and continued to breastfeed from both breasts. She was not able to utilize an electric pump to express milk from her left breast due to discomfort and minimal milk extraction. She did report that the baby latched comfortably with audible swallows from the left breast, but she felt there was less milk production than from the right breast. The patient also felt she produced less milk in comparison to previously breastfeeding her other two children for 1 year without requiring infant formula. Beginning at 2 weeks postpartum, at the recommendation of the pediatrician, the patient initiated infant formula to maintain appropriate weight gain in the current infant. The infant had regained birthweight at two and a half weeks post- partum. Due to her left breast pain and swelling, the patient also restarted prednisone at 20 mg by mouth daily at 2 weeks postpartum.
She presented at 4 weeks postpartum to the breast surgeon for evaluation of worsening redness and pain in the left breast despite being compliant with prednisone. She noticed increased difficulty with her infant’s latch on the affected breast due to pain, as well as decreased swallows that she felt corresponded to decreased breastmilk volume. On exam, a large mass-like area with erythema and induration in the left breast was appreciated. This extended from the 9:00 to 4:00 position in the periareolar region, measuring approximately 8.0 × 8.0 × 9.0 cm total size. There was no fistula present.
The patient elected to undergo tapered discontinuation of her oral steroid over the course of 1 week and injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine into the affected areas of her left breast. Due to long-acting depot mechanism and high transfer of triamcinolone into breastmilk, the breast surgeon advised her to discontinue breastfeeding from the affected breast; triamcinolone was expected to remain in the breast for 3 weeks until the time of the next injection [17]. She initiated pumping on the unaffected right breast to stimulate increased production and continued to provide the infant with additional formula supplementation as needed. At the advice of her breast surgeon, she started galactagogues with brewer’s yeast and moringa three times daily. She used ibuprofen and acetaminophen as needed for pain, as well as warm compresses and ice. Her milk production on the left breast was low, and she did not require hand expression to relieve engorgement.
On follow up 3 weeks later, the patient had developed right nipple pain. This pain was considered related to increased engorgement in the right breast, as well as, the infant clamping in adjustment to increased flow of unilateral milk. The patient was instructed in lymphatic massage and utilized a laid-back breastfeeding position to reduce velocity of flow in the right breast [18, 19].
Her left breast pain had improved, and the mass had decreased in size to 6.0 × 6.0 × 5.0 cm from 11:00–3:00. She had developed a new draining fistula in the 1:00 position. An additional 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was injected into the affected areas of her left breast.
At 10 weeks postpartum (6 weeks after presentation to the breast surgeon), the patient indicated that she would like to attempt to resume breastfeeding from the affected left breast. On examination, the fistula was closed and there was a decreased mass-like area in the left breast to approximately 4.0 × 3.0 × 2.0 cm size. Therefore, no steroid injection was performed. The images showing the difference in volume between her right and left breasts at this time is demonstrated in Fig. 1. Comparison images demonstrating improvement in her left breast are illustrated in Fig. 2. Fig. 1 At 10 weeks postpartum, the left breast affected by IGM is no longer lactating; right breast is lactating
Fig. 2 a Left breast affected by IGM at week 3 after presentation (7 weeks postpartum) and (a) Left breast affected by IGM at week 6 after presentation (10 weeks postpartum)
Three weeks later, the patient presented with increased redness and pain in the previously affected left breast. The patient had attempted breastfeeding from the left breast, but had stopped due to pain and low milk production. A new fistula in the 1:00 position and developed with new erythema and fluctuance in the 7:00 position with an associated new 2.0 × 2.0 × 1.0 cm mass-like area. An injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was performed into the 1:00 and 7:00 positions of the left breast and she was advised to stop breastfeeding from the left breast after the injection.
At three-week follow-up, the patient had developed a new 9:00 position fistula, but there was decreased mass-like effect and erythema in the remainder of the breast. She elected to resume breastfeeding from the left breast and start and oral prednisone taper over 6 days, 30 mg of prednisone per day, tapering to 5 mg per day. She noticed gradual decrease in erythema and fluctuance and no new fistulae. She continued to breastfeed from both breasts until 7 months postpartum. At this point, she stopped breastfeeding due to gradual decrease in milk production over time.
Discussion and conclusions
Presentation
In all patients, whether lactating or not, IGM is a challenging clinical scenario to manage, particularly since many women experience a protracted waxing and waning course of symptoms. Some patients may present with a mass alone that spontaneously regresses, whereas others demonstrate significant erythema, fluid collection formation, and recurrent fistulization from the onset of the disease [20].
Most symptomatology is localized to the periareolar region extending outward [21]. As one area of inflammation becomes more quiescent, new disease may present in a new quadrant of the breast [20]. Without any intervention, the IGM generally will resolve within a few years of presentation [22]. With systemic immunosuppression with methotrexate and/or azathioprine, the disease tends to subside earlier. However, patients may experience a flare months after apparent resolution [10, 23]. Importantly, azathioprine has a good safety profile in pregnancy and lactation [24].
Evaluation and diagnosis
All patients with suspected IGM require breast imaging and core needle biopsy to confirm diagnosis; this is safe in breastfeeding [2]. Tuberculosis should be ruled out [25] and patients should be referred to a rheumatologist to rule out underlying autoimmune disorder. The relationship with erythema nodosum and IGM is unclear, but it has been hypothesized that it can represent an extra-mammary form of IGM [26].
General principles of treatment
In the non-lactating population, traditional treatment has included systemic steroids, methotrexate and antibiotics, local care involves procedures ranging from incision and drainage, wide local excision with wound vacuum placement, or mastectomy [2, 27]. A systematic review of 3060 patients found that more industrialized countries use surgery more frequently, and more rural countries have a tendency to rely more heavily on antibiotics [28]. Regardless of location, steroids are often used, and it is common for IGM to require a combination of several therapies [28]. A large study of IGM that investigated 206 individuals in Iran recommends corticosteroids as first line treatment for this disease [3]. There are reports of surgical management with improved cosmetic outcomes and minimal complications, including mastectomy with immediate reconstruction, but there is also report of surgery causing increased inflammatory reaction and fistulazation [7, 10, 29]. While anti-tuberculosis agents such as rifampin have been utilized, they also have been associated with rebound inflammation [30, 31].
Cultures of fluid collections often demonstrate Corynebacterium, Streptococci, Staphylococci or Bacteroides; however, the traditionally utilized antibiotics of doxycycline and trimethoprim-sulfamethoxazole have not shown clinically significant results in terms of disease severity or duration [32, 33]. This is likely related to the thought that IGM is an inflammatory rather than infectious disease, and culture results reflect the presence of common breast flora [34]. More recently, IGM has been thought to have a significant autoimmune component, which supports the notion that localized steroids could be an effective treatment strategy [31].
Surgical intervention also remains controversial. While one study demonstrates a shortened duration to resolution compared with steroid injections and observation alone, not all cases require such aggressive treatment [9]. More recently, it has become clear that repeated surgical intervention can potentiate inflammation and can increase disease severity [35]. One group compared recurrence for individuals who were treated with antibiotics and wide local excision, or incision and drainage plus steroids. The less invasive approach had significantly less recurrence [35]. A retrospective study that demonstrated excision had a lower recurrence rate than the comparison group. However, this study was limited in that the comparison underwent warm compress, herb application, and drainage alone; this conservative approach without steroids would not be expected to treat the disease effectively [36].
Instead of traditional invasive approaches that have not demonstrated clear success, intralesional triamcinolone injections every 1–2 weeks represent a promising minimally invasive approach with limited systemic side effects and good outcomes [37]. After the first steroid injection, patients experience a marked decrease in disease volume, symptoms, and frequency of recurrence [37]. Additionally, patients who receive steroid injections were likely to achieve a complete recovery without the adverse effects of oral steroids [37]. The frequency of injection can be adapted based on clinical circumstances, such as severity of presentation.
While triamcinolone injection directly into breast lesions can relieve symptoms, due to the potential for infant exposure to the steroid via breast milk, this treatment modality is not compatible with continued breastfeeding on the treated breast(s). This is related to high oral dose to infant and the potential infant side effects of growth suppression, and interference with corticosteroid production [17]. The procedure for intralesional injection is outlined below, and can be performed with or without ultrasound guidance with an 18-gauge needle. Clean skin
Aspirate any existing fluid
Mix 40 mg/ 1 mL triamcinolone with 3 mL 2% lidocaine for a total volume of 4 mL
Inject deeply into areas of active fistula, mass, erythema or induration.
Wound care should consist of managing drainage from fistulae with gauze and other non-adherent dressings. Tape should be avoided due to further abrasion and irritation of skin. Patients often experience significant distress related to the symptoms of the disease and psychosocial support should be provided.
Treatment during lactation
There is no data to suggest that breastfeeding prolongs the duration of symptoms of IGM, and the diagnosis of IGM does not preclude lactation. Interestingly, a recent study demonstrated a small minority of IGM patients, not in the lactational period, who have demonstrated elevated prolactin from either dopamine antagonist medications or a prolactinoma [38]. Like much of other proposed pathophysiologic mechanisms in IGM, the exact relationship to prolactin remains unclear.
Special considerations for treatment for breastfeeding women include the fact that oral steroids decrease milk production [39]. Maternal insomnia, agitation, and risk for depression also are of concern in the postpartum population [39, 40]. Triamcinolone injections in the breast are contraindicated with breastfeeding from that breast for approximately 2 weeks [17]. In high doses such as those used with anti-neoplastic therapy, methotrexate is not compatible with breastfeeding. Limited information suggests that single or weekly doses may demonstrate low levels of methotrexate in breastmilk, but some expert opinions also warn against this use during lactation [41]. Azathioprine as studied primarily in inflammatory bowel disease populations, is safe during lactation, may provide more ideal systemic therapy in the breastfeeding population [42].
We recommend individualized care with considerations given to the following options: Continuing oral steroids with knowledge oral steroids may not be particularly effective. Systemic steroids cause known side effects as outlined above, including reduction in milk production, insomnia, agitation, and depression, however low-dose or even higher doses for a short duration are likely compatible with lactation [39].
Avoiding use of methotrexate, which is generally incompatible with lactation. Consideration of azathioprine, which is compatible with lactation.
Stopping breastfeeding and pumping from the affected breast, augmenting production on the unaffected breast, and utilizing intralesional triamcinolone injections on the affected breast.
Not utilizing steroids and managing patients with supportive care only, such as gauze for draining fistulae to keep skin dry and minimize maceration.
Pain management including non-steroidal anti-inflammatory medications such as ibuprofen and acetaminophen, as well as conservative management with ice and heat per patient comfort.
Repeated antibiotic treatments are not effective and can result in unintended and avoidable side effects, such as Clostridium difficile infections, gastrointestinal distress and future resistance.
Psychosocial support for patient distress and discomfort
Lactation consultant (IBCLC) involvement or other breastfeeding specialist to assist in unilateral weaning, to assure adequate milk supply and to offer breastfeeding support.
In conclusion, IGM is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the side effects of systemic steroids; the need to wean a breast being treated with intralesional steroids; and, augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Abbreviations
IGM Idiopathic Granulomatous Mastitis
NAC Nipple Areolar Complex
Acknowledgements
None.
Authors’ contributions
All authors wrote, read and approved the final manuscript. Dr. Katrina Mitchell took care of and treated the patient.
Funding
Not Applicable.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
This study was IRB Approved at the Presbyterian Hospital Albuquerque, New Mexico after direct consent was obtained from the patient.
Consent for publication
The patient is aware, and accepting, of her case being submitted for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33663552 | 20,160,158 | 2021-03-04 |
What was the administration route of drug 'PREDNISONE'? | Management of idiopathic granulomatous mastitis in lactation: case report and review of the literature.
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition that mimics two common breast disorders: breast carcinoma and breast abscess. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and can significantly impact lactation. Despite the prevalence of this disease, no current literature describes an approach to managing IGM during breastfeeding.
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with worsening left breast swelling and redness. She underwent a mammogram, ultrasound and core needle biopsy that confirmed the diagnosis of Idiopathic Granulomatous Mastitis. During the postpartum period, she underwent intralesional triamcinolone injections of her left breast. Due to the contraindication of breastfeeding after local steroid injection, the patient stopped breastfeeding from the affected breast and continued breastfeeding unilaterally.
Idiopathic Granulomatous Mastitis is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Treatment of IGM during pregnancy and lactation has thus far not been addressed. We review the literature on the treatment of IGM in the non-lactating population, and propose considerations for treating breastfeeding women affected by this disease. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the following: side effects of systemic steroids, the need to wean a breast being treated with intralesional steroids, and augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Background
Idiopathic Granulomatous Mastitis (IGM) is a benign chronic inflammatory breast condition, first described in 1972 by Kessler and Wooloch, that mimics two common breast disorders: breast carcinoma and breast abscess [1]. It can form breast masses, fistulae, and fluid collections, resulting in breast disfigurement with retraction and nipple areolar complex (NAC) and inversion. IGM most often presents in women of childbearing age within a few years of pregnancy, and is most common in women of Hispanic, Asian, Middle Eastern or African origin [2, 3]. Evaluation involves breast imaging with ultrasound and mammogram, and core needle biopsy to establish a diagnosis [4].
In the past, treatment of IGM involved incision and drainage of fluid collections, extensive debridement, mastectomy, as well as oral steroids, methotrexate and other anti-inflammatories including colchicine [5–7]. More recent management has shifted to minimally invasive approaches, including aspiration of fluid and intralesional injection of steroids [8, 9]. Additionally, methotrexate and azathioprine can be used as steroid-sparing agents and help promote long-term remission [10].
There is no consensus in the field regarding optimal management, even in non-lactating patients. Some of the uncertainty in treatment might come from uncertainty in causation. IGM has been thought of as infectious, inflammatory and autoimmune [11]. Recently, a few studies using low dose prednisone, 25 mg/day and 0.8 mg/kg/day have been shown effective in treatment of disease, supporting a more inflammatory or autoimmune etiology [12–14]. There is some suggestion that Corynebacterium kroppenstedtii is associated with IGM; however, there is no evidence that targeting these bacteria alters the disease course and may reflect normal breast microbiome [15, 16].
Treatment during breastfeeding poses a particular challenge in terms of managing symptoms and protecting lactation, though no current literature describes the approach to this clinical scenario. We describe the experience of a patient diagnosed during pregnancy with IGM, and her management during lactation. We review the literature on the treatment of IGM in the non-lactating population, and propose guidelines for treating breastfeeding women affected by this disease.
Case presentation
A 28-year-old G3P2 patient of Native American origin presented to her obstetrician at 7 months pregnant with several months of left breast swelling and redness. At the recommendation of her obstetrician, she underwent diagnostic mammogram and ultrasound showing an ill-defined hypoechoic mass-like area in the left breast 10:00 position, 4 cm from the nipple. Core needle biopsy demonstrated granulomatous mastitis. She also had developed erythema nodosum on her bilateral lower extremities during pregnancy. Tuberculosis was ruled out. Evaluation for autoimmune disease, including serology, was negative. Her obstetrician started a steroid taper at 30 mg per day for a 6 day course, decreasing by 5 mg per day. The patient experienced improvement in pain and swelling during this time. This taper concluded 3 weeks prior to delivery; no further steroids were prescribed in order prevent hematologic or infectious complications at birth.
The patient began breastfeeding after delivery and continued to breastfeed from both breasts. She was not able to utilize an electric pump to express milk from her left breast due to discomfort and minimal milk extraction. She did report that the baby latched comfortably with audible swallows from the left breast, but she felt there was less milk production than from the right breast. The patient also felt she produced less milk in comparison to previously breastfeeding her other two children for 1 year without requiring infant formula. Beginning at 2 weeks postpartum, at the recommendation of the pediatrician, the patient initiated infant formula to maintain appropriate weight gain in the current infant. The infant had regained birthweight at two and a half weeks post- partum. Due to her left breast pain and swelling, the patient also restarted prednisone at 20 mg by mouth daily at 2 weeks postpartum.
She presented at 4 weeks postpartum to the breast surgeon for evaluation of worsening redness and pain in the left breast despite being compliant with prednisone. She noticed increased difficulty with her infant’s latch on the affected breast due to pain, as well as decreased swallows that she felt corresponded to decreased breastmilk volume. On exam, a large mass-like area with erythema and induration in the left breast was appreciated. This extended from the 9:00 to 4:00 position in the periareolar region, measuring approximately 8.0 × 8.0 × 9.0 cm total size. There was no fistula present.
The patient elected to undergo tapered discontinuation of her oral steroid over the course of 1 week and injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine into the affected areas of her left breast. Due to long-acting depot mechanism and high transfer of triamcinolone into breastmilk, the breast surgeon advised her to discontinue breastfeeding from the affected breast; triamcinolone was expected to remain in the breast for 3 weeks until the time of the next injection [17]. She initiated pumping on the unaffected right breast to stimulate increased production and continued to provide the infant with additional formula supplementation as needed. At the advice of her breast surgeon, she started galactagogues with brewer’s yeast and moringa three times daily. She used ibuprofen and acetaminophen as needed for pain, as well as warm compresses and ice. Her milk production on the left breast was low, and she did not require hand expression to relieve engorgement.
On follow up 3 weeks later, the patient had developed right nipple pain. This pain was considered related to increased engorgement in the right breast, as well as, the infant clamping in adjustment to increased flow of unilateral milk. The patient was instructed in lymphatic massage and utilized a laid-back breastfeeding position to reduce velocity of flow in the right breast [18, 19].
Her left breast pain had improved, and the mass had decreased in size to 6.0 × 6.0 × 5.0 cm from 11:00–3:00. She had developed a new draining fistula in the 1:00 position. An additional 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was injected into the affected areas of her left breast.
At 10 weeks postpartum (6 weeks after presentation to the breast surgeon), the patient indicated that she would like to attempt to resume breastfeeding from the affected left breast. On examination, the fistula was closed and there was a decreased mass-like area in the left breast to approximately 4.0 × 3.0 × 2.0 cm size. Therefore, no steroid injection was performed. The images showing the difference in volume between her right and left breasts at this time is demonstrated in Fig. 1. Comparison images demonstrating improvement in her left breast are illustrated in Fig. 2. Fig. 1 At 10 weeks postpartum, the left breast affected by IGM is no longer lactating; right breast is lactating
Fig. 2 a Left breast affected by IGM at week 3 after presentation (7 weeks postpartum) and (a) Left breast affected by IGM at week 6 after presentation (10 weeks postpartum)
Three weeks later, the patient presented with increased redness and pain in the previously affected left breast. The patient had attempted breastfeeding from the left breast, but had stopped due to pain and low milk production. A new fistula in the 1:00 position and developed with new erythema and fluctuance in the 7:00 position with an associated new 2.0 × 2.0 × 1.0 cm mass-like area. An injection of 40 mg/1 mL triamcinolone mixed with 3 mL 2% lidocaine was performed into the 1:00 and 7:00 positions of the left breast and she was advised to stop breastfeeding from the left breast after the injection.
At three-week follow-up, the patient had developed a new 9:00 position fistula, but there was decreased mass-like effect and erythema in the remainder of the breast. She elected to resume breastfeeding from the left breast and start and oral prednisone taper over 6 days, 30 mg of prednisone per day, tapering to 5 mg per day. She noticed gradual decrease in erythema and fluctuance and no new fistulae. She continued to breastfeed from both breasts until 7 months postpartum. At this point, she stopped breastfeeding due to gradual decrease in milk production over time.
Discussion and conclusions
Presentation
In all patients, whether lactating or not, IGM is a challenging clinical scenario to manage, particularly since many women experience a protracted waxing and waning course of symptoms. Some patients may present with a mass alone that spontaneously regresses, whereas others demonstrate significant erythema, fluid collection formation, and recurrent fistulization from the onset of the disease [20].
Most symptomatology is localized to the periareolar region extending outward [21]. As one area of inflammation becomes more quiescent, new disease may present in a new quadrant of the breast [20]. Without any intervention, the IGM generally will resolve within a few years of presentation [22]. With systemic immunosuppression with methotrexate and/or azathioprine, the disease tends to subside earlier. However, patients may experience a flare months after apparent resolution [10, 23]. Importantly, azathioprine has a good safety profile in pregnancy and lactation [24].
Evaluation and diagnosis
All patients with suspected IGM require breast imaging and core needle biopsy to confirm diagnosis; this is safe in breastfeeding [2]. Tuberculosis should be ruled out [25] and patients should be referred to a rheumatologist to rule out underlying autoimmune disorder. The relationship with erythema nodosum and IGM is unclear, but it has been hypothesized that it can represent an extra-mammary form of IGM [26].
General principles of treatment
In the non-lactating population, traditional treatment has included systemic steroids, methotrexate and antibiotics, local care involves procedures ranging from incision and drainage, wide local excision with wound vacuum placement, or mastectomy [2, 27]. A systematic review of 3060 patients found that more industrialized countries use surgery more frequently, and more rural countries have a tendency to rely more heavily on antibiotics [28]. Regardless of location, steroids are often used, and it is common for IGM to require a combination of several therapies [28]. A large study of IGM that investigated 206 individuals in Iran recommends corticosteroids as first line treatment for this disease [3]. There are reports of surgical management with improved cosmetic outcomes and minimal complications, including mastectomy with immediate reconstruction, but there is also report of surgery causing increased inflammatory reaction and fistulazation [7, 10, 29]. While anti-tuberculosis agents such as rifampin have been utilized, they also have been associated with rebound inflammation [30, 31].
Cultures of fluid collections often demonstrate Corynebacterium, Streptococci, Staphylococci or Bacteroides; however, the traditionally utilized antibiotics of doxycycline and trimethoprim-sulfamethoxazole have not shown clinically significant results in terms of disease severity or duration [32, 33]. This is likely related to the thought that IGM is an inflammatory rather than infectious disease, and culture results reflect the presence of common breast flora [34]. More recently, IGM has been thought to have a significant autoimmune component, which supports the notion that localized steroids could be an effective treatment strategy [31].
Surgical intervention also remains controversial. While one study demonstrates a shortened duration to resolution compared with steroid injections and observation alone, not all cases require such aggressive treatment [9]. More recently, it has become clear that repeated surgical intervention can potentiate inflammation and can increase disease severity [35]. One group compared recurrence for individuals who were treated with antibiotics and wide local excision, or incision and drainage plus steroids. The less invasive approach had significantly less recurrence [35]. A retrospective study that demonstrated excision had a lower recurrence rate than the comparison group. However, this study was limited in that the comparison underwent warm compress, herb application, and drainage alone; this conservative approach without steroids would not be expected to treat the disease effectively [36].
Instead of traditional invasive approaches that have not demonstrated clear success, intralesional triamcinolone injections every 1–2 weeks represent a promising minimally invasive approach with limited systemic side effects and good outcomes [37]. After the first steroid injection, patients experience a marked decrease in disease volume, symptoms, and frequency of recurrence [37]. Additionally, patients who receive steroid injections were likely to achieve a complete recovery without the adverse effects of oral steroids [37]. The frequency of injection can be adapted based on clinical circumstances, such as severity of presentation.
While triamcinolone injection directly into breast lesions can relieve symptoms, due to the potential for infant exposure to the steroid via breast milk, this treatment modality is not compatible with continued breastfeeding on the treated breast(s). This is related to high oral dose to infant and the potential infant side effects of growth suppression, and interference with corticosteroid production [17]. The procedure for intralesional injection is outlined below, and can be performed with or without ultrasound guidance with an 18-gauge needle. Clean skin
Aspirate any existing fluid
Mix 40 mg/ 1 mL triamcinolone with 3 mL 2% lidocaine for a total volume of 4 mL
Inject deeply into areas of active fistula, mass, erythema or induration.
Wound care should consist of managing drainage from fistulae with gauze and other non-adherent dressings. Tape should be avoided due to further abrasion and irritation of skin. Patients often experience significant distress related to the symptoms of the disease and psychosocial support should be provided.
Treatment during lactation
There is no data to suggest that breastfeeding prolongs the duration of symptoms of IGM, and the diagnosis of IGM does not preclude lactation. Interestingly, a recent study demonstrated a small minority of IGM patients, not in the lactational period, who have demonstrated elevated prolactin from either dopamine antagonist medications or a prolactinoma [38]. Like much of other proposed pathophysiologic mechanisms in IGM, the exact relationship to prolactin remains unclear.
Special considerations for treatment for breastfeeding women include the fact that oral steroids decrease milk production [39]. Maternal insomnia, agitation, and risk for depression also are of concern in the postpartum population [39, 40]. Triamcinolone injections in the breast are contraindicated with breastfeeding from that breast for approximately 2 weeks [17]. In high doses such as those used with anti-neoplastic therapy, methotrexate is not compatible with breastfeeding. Limited information suggests that single or weekly doses may demonstrate low levels of methotrexate in breastmilk, but some expert opinions also warn against this use during lactation [41]. Azathioprine as studied primarily in inflammatory bowel disease populations, is safe during lactation, may provide more ideal systemic therapy in the breastfeeding population [42].
We recommend individualized care with considerations given to the following options: Continuing oral steroids with knowledge oral steroids may not be particularly effective. Systemic steroids cause known side effects as outlined above, including reduction in milk production, insomnia, agitation, and depression, however low-dose or even higher doses for a short duration are likely compatible with lactation [39].
Avoiding use of methotrexate, which is generally incompatible with lactation. Consideration of azathioprine, which is compatible with lactation.
Stopping breastfeeding and pumping from the affected breast, augmenting production on the unaffected breast, and utilizing intralesional triamcinolone injections on the affected breast.
Not utilizing steroids and managing patients with supportive care only, such as gauze for draining fistulae to keep skin dry and minimize maceration.
Pain management including non-steroidal anti-inflammatory medications such as ibuprofen and acetaminophen, as well as conservative management with ice and heat per patient comfort.
Repeated antibiotic treatments are not effective and can result in unintended and avoidable side effects, such as Clostridium difficile infections, gastrointestinal distress and future resistance.
Psychosocial support for patient distress and discomfort
Lactation consultant (IBCLC) involvement or other breastfeeding specialist to assist in unilateral weaning, to assure adequate milk supply and to offer breastfeeding support.
In conclusion, IGM is a challenging chronic inflammatory breast disease that affects women primarily in the reproductive years, with a higher incidence in patients of Hispanic, Native American, Middle Eastern, and African descent. Traditional treatment has included systemic immunosuppression and surgery, but newer literature demonstrates that intralesional injection of steroid can provide significant symptomatic relief to patients. A diagnosis of IGM does not preclude breastfeeding, though patients may experience challenges with milk production and latch on the affected breast. Individualized care should be provided, with considerations given to the side effects of systemic steroids; the need to wean a breast being treated with intralesional steroids; and, augmentation of milk production on the unaffected breast to promote continued breastfeeding.
Abbreviations
IGM Idiopathic Granulomatous Mastitis
NAC Nipple Areolar Complex
Acknowledgements
None.
Authors’ contributions
All authors wrote, read and approved the final manuscript. Dr. Katrina Mitchell took care of and treated the patient.
Funding
Not Applicable.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
This study was IRB Approved at the Presbyterian Hospital Albuquerque, New Mexico after direct consent was obtained from the patient.
Consent for publication
The patient is aware, and accepting, of her case being submitted for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33663552 | 20,102,115 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Corneal perforation'. | Controversy of indomethacin eye drops in the treatment of rheumatoid arthritis-induced corneal ulceration: a case report.
BACKGROUND
Perforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA). Addressing a perforated cornea associated with RA is challenging, since its pathogenesis is not fully elucidated. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) were developed to prevent cystoid macular edema following cataract surgery in patients at risk. Their prescription in inflammation of the anterior segment of the eye may induce negative effects on the ocular surface. We bring into focus a corneal perforation in a patient with RA who used indomethacin eye drops to treat corneal ulceration, but responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our aim is to emphasize two issues: the contraindication of topical indomethacin in corneal defects, and the immediate positive impact of topical cyclosporine 0.1% on corneal healing.
METHODS
A 73-year-old Caucasian woman with a 13-year history of RA was treated for corneal ulceration in her oculus sinister (OS) with topical indomethacin and gentamicin. The patient was being treated with systemic immunosuppression and NSAIDs for the underlying RA and artificial tears in both eyes. No bandage contact lens was used. After 3 weeks of treatment, perforation of the left cornea occurred and the patient was referred to our hospital. Upon admission, visual acuity (VA) in the OS was 20/630. Slit lamp examination of the OS revealed paracentral corneal perforation, iris plugging the perforation site, shallow anterior chamber, clear aqueous humor, and clear lens. Anterior segment optical coherence tomography showed the inclavated iris in the perforation site and minimum corneal thickness of 101 µm. Topical NSAIDs were discontinued and topical treatment was initiated with tobramycin, tropicamide 1%, phenylephrine 10%, and artificial tears five times a day, and occlusive patch. For 5 days, there was no improvement, so topical cyclosporine 0.1% was started, one drop every evening. Within 7 days, the cornea had healed, the iris was liberated from the perforation site, the minimum corneal thickness increased to 250 µm, VA improved to 20/25, and the patient was free of symptoms.
CONCLUSIONS
The main "takeaway" lessons from this case are that topical indomethacin should not be prescribed in cases of inflammation of the anterior segment of the eye, and that topical cyclosporine was efficacious in healing corneal perforation in our patient.
Background
Perforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA) [1, 2]. This paper reports the case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin prior to admission to our hospital. Although the pathogenesis of corneal perforation is complex [1, 2], we aim to call attention to the potentially devastating effects of topical indomethacin on the cornea, if not properly indicated [3, 4]. Topical nonsteroidal anti inflammatory drugs (NSAIDs) are designed to prevent cystoid macular edema after cataract surgery in patients at risk, not to treat inflammation of the anterior segment of the eye [3, 4]. Unfortunately, some eye care physicians prescribe them routinely for inflammation of the anterior segment of the eye, with potential side effects, among which corneal perforation is the most severe. We bring into focus a case of corneal perforation in a patient with RA with prolonged use of topical indomethacin, but who responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our case joins a few other reports in the literature related to the occurrence of severe corneal lesions following prolonged topical treatment with NSAIDs, sounding a warning signal on their accurate indication [3, 4]. We also emphasize the immediate positive effect of topical cyclosporine 0.1% on the corneal healing process.
Informed consent was obtained from the patient regarding the publication of this case and the related images.
Case presentation
A 73-year-old Caucasian woman with a 13-year history of RA complained of a marked decrease in visual acuity (VA) and intense pain in her oculus sinister (OS), which was red, accompanied by a sensation of hot leakage on her cheek, approximately 12 hours before admission to our hospital. For the past 3 weeks she had been treated in another service with gentamicin drops and indomethacin drops four times a day for a previously diagnosed corneal ulceration of the OS. No bandage contact lens was used. Before this episode, the patient did not have regular ophthalmological follow-ups. The patient had no history of hypertension or diabetes.
The patient was using methotrexate 2.5 mg three times a week for treatment of RA. For the dry eye syndrome, preservative-free lubricants were prescribed.
Upon ophthalmic examination, visual acuity (VA) was 20/32 in the oculus dexter (OD) and 20/630 in the OS. Slit lamp examination revealed subtle conjunctival congestion with fine stromal opacities in the OD, and in the OS, moderate ciliary injection, a perforated paracentral corneal ulceration approximately 1 mm in diameter, with a dense perilesional infiltrate, stromal melting, and a few corneal new vessels and stromal opacities around it (Fig. 1). The pupil was peaked but reactive and the iris was plugging the perforation. A shallow, almost flat anterior chamber with clear aqueous humor and a clear lens were found (Fig. 1). No abnormality was noted in the fundus examination of the eyes. Anterior segment optical coherence tomography (OCT, Heidelberg Spectralis) revealed the inclavated iris in the ulceration zone and a thin cornea in the OS and an imminent 100 µm minimum corneal thickness at the site of perforation (Fig. 2).Fig. 1 Slit lamp examination: perforated paracentral corneal ulceration, with dense perilesional infiltrate, stromal melting, a few corneal new vessels and stromal opacities, shallow anterior chamber, clear aqueous humor, iris plugging the corneal perforation
Fig. 2 Anterior segment optical coherence tomography (Heidelberg Spectralis): corneal thinning (minimum corneal thickness 101 µm), iris plugging the perforation site
Ophthalmological evaluation led us to the diagnosis of paracentral corneal perforation.
Systemic treatment with Ceftriaxone was initiated, 1 g every 12 hours, and topical medication was modified to tobramycin hourly, mydriasis with tropicamide and phenylephrine five times a day, lubricants, and occlusive patch.
Evolution under treatment was stationary without signs of improvement. Therefore, 5 days after admission, cyclosporine 1 mg/ml was added to the topical treatment and it was administered 1 drop a day in the evening. Treatment with Methotrexate 7.5 mg/week was continued.
The danger of this sight-threatening situation required rheumatologist expertise. Taking into account the lack of general symptoms and the normal values of C reactive protein and ESR, neither pulse therapy with methylprednisolone, nor cyclophosphamide addition were taken into consideration.
Fortunately, visual acuity started to improve to 20/63, the perilesional infiltrate decreased in size and depth, the iris was liberated from the perforation site and the corneal transparency improved (Fig. 3). At discharge, VA in the OS was 20/25 and the patient was free of symptoms.Fig. 3. Slit lamp examination of the left eye 7 days following treatment: corneal perforation sealed, dense perilesional infiltrate, and stromal melting diminished considerably, anterior chamber has normal depth
Anterior segment optical coherence tomography showed an increase in minimum corneal thickness to 250 µm (Fig. 4). We performed a Schirmer test without anesthesia in the OD, and the result was 1 mm at 5 minutes.Fig. 4. Anterior segment optical coherence tomography of the left eye 7 days after treatment (Heidelberg Spectralis): minimum corneal thickness of 250 µm, iris liberated from the perforation site
After having been discharged, the patient continued topical treatment with tobramycin three times/day and cyclosporine 1mg/ml, one drop/day every evening and preservative-free eye lubricants; 6 months after this episode, the patient experienced no further ocular complains, her vision is 20/20 in both eyes, she is under rheumatologic and ophthalmological supervision and keeps using preservative-free ocular lubricants.
Discussion and conclusions
Rheumatoid arthritis (RA), a chronic systemic autoimmune inflammatory entity, is one of the most common collagen vascular diseases. It affects 3–5% of the adult population, more frequently women than men, with an average age at onset of 35–40 years [1]. RA can affect the eye at multiple levels: anterior segment (keratoconjunctivitis sicca, punctate keratopathy, keratitis, episcleritis, scleritis), extraocular muscles, and posterior segment (choroid, retina, optic nerve) [1]. About 90% of patients with RA suffer from dry eye syndrome, especially keratoconjunctivitis sicca, which seems to be correlated with a disease course longer than 10 years [2]. With regard to corneal involvement, many types of keratitis have been described in RA, including peripheral limbal furrow, peripheral or paracentral ulcerative keratitis, keratolysis, acute stromal keratitis, and sclerosing keratitis.
We bring into discussion a case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin, which we managed to treat satisfactorily using a medical approach. Establishing the etiological diagnosis was challenging in this case, and most likely there are several implicating factors: RA definitely plays the main role through modification of the corneal structure and the associated ocular dryness, but the prolonged treatment with topical indomethacin cannot be ruled out, at least at the secondary level.
The pathogenesis of RA-associated corneal ulceration is far from fully elucidated [1]. It seems to be an imbalance between matrix metalloproteinases (MMP) such as MMP-2 in the corneal stroma and MMP-9 in the lacrimal glands and tissue inhibitors of matrix metalloproteinases (TIMP-1) [1, 2, 4]. Reduced levels of TIMP-1 are responsible for high collagenase activity that leads to a keratolytic sterile process [2]. A resulting altered epithelial barrier facilitates the entrance of inflammatory mediators such as monocytes and macrophages in the stroma that subsequently leads to activation of T cells, resulting in production of antibodies and formation of immune complexes. There seems to be significant human leukocyte antigen–DR isotype (HLA-DR) expression by stromal keratocytes and epithelium determined by interferon gamma released by TH2 lymphocytes [1]. Local cytokines such as interleukin-1 and tumor necrosis factor-alpha induce production of collagenase and protease [1, 2, 5, 6]. Paracentral ulcerative keratitis develops in patients with severe dry eye but without marked conjunctival inflammation, such as our case [1, 2].
The initiation of topical cyclosporine therapy was the key to successful treatment given that it arrested the keratolysis and led to ulcer re-epithelialization [7]. There are several reports that recommend topical cyclosporine for corneal ulcer associated with RA [7, 8], as it may enable epithelial healing while reducing cell-mediated immune reactions in the cornea [9]. In our case, topical cyclosporine was initiated with a 5-day delay, as it is expensive and not immediately available. Before the administration of topical cyclosporine, the corneal ulcer did not show significant improvement. Regarding systemic chemotherapy in rheumatoid corneal perforations, there are no clear guidelines, but a strong collaboration between ophthalmologists and rheumatologists is essential to assess the systemic disease status and to determine the need to change or adjust the immunosuppressive therapy.
Although the patient was on immunosuppressive treatment and free of systemic symptoms, she still developed corneal ulceration, highlighting the fact that there are several events initiating corneal lesions and others perpetuating them, such as infection that accelerates corneal melting [5].
The previously diagnosed dry eye syndrome in the context of RA, even under treatment with preservative-free lubricants, favored the ulceration development [8]. There are studies showing that the corneal central thickness and stromal thickness in patients with RA are statistically significantly lower than in controls [1, 2]. Additionally, there is evidence of proteolytic degradation in both corneas of patients ranging from early xerophthalmia to ulcerating xerophthalmia [1, 8].
The use of topical indomethacin in our case is questionable [4, 10]. There have been case reports with patients taking topical NSAIDs who developed corneal perforation that healed after discontinuation [3, 4]. Moreover, it has been shown that topical NSAIDs are associated with corneal hypoesthesia and may be responsible for corneal perforation [3, 4].
Even if the clinical aspect was suggestive of sterile ulcerative keratitis (clear cornea and aqueous), treating the condition exclusively as an autoimmune corneal melt without antibiotic coverage could have resulted in a potentially blinding condition [5]. For logistical reasons we did not have the ability to perform corneal scraping, and therefore we chose topical and systemic treatment with broad-spectrum antibiotics.
Considering the positive outcome following topical cyclosporine, the role of inflammation proved to be essential.
In cases with perforation, the application of cyanoacrylate adhesive, lamellar grafting, or tarsorrhaphy is indicated, depending on ulceration size [1]. In our case, the presence of the iris at the ulceration site acted like a self-adhesive substance.
Nevertheless, photographs of the lesion were helpful in evaluating regression. Anterior segment OCT images were particularly important, highlighting the anatomical improvement.
Corneal perforated ulceration is a rare complication secondary to RA. This case signals and demonstrates that even though the underlying disease was well controlled and monitored, and the dry eye was properly addressed, corneal ulceration still occurred in this RA patient. Indomethacin administered topically may have precipitated corneal perforation, but cyclosporine associated with antibiotics led to good visual outcome. However, since the patient had already been diagnosed with corneal ulcer in another service, there is a possibility that the corneal perforation was a natural course of peripheral ulcerative keratitis (PUK) and undertreatment, rather than due to indomethacin drops. Establishing a cause-effect relationship in this scenario when natural course of the disease is a major confounding factor is difficult and the assumption that indomethacin is the sole culprit here is questionable. Methotrexate 7.5 mg/week is the usual lowest prescribed dose in PUK. Therefore, we can assume that the progression of the ulcer might have been prevented by increasing the methotrexate dose or by adding systemic steroids.
Anterior segment OCT has demonstrated its valuable role in monitoring the disease from a structural perspective.
The main “takeaway” lessons from this case are that topical indomethacin should not be used in corneal ulcers, and that topical cyclosporine was efficacious in healing corneal perforation in a patient with RA.
Abbreviations
ESR Erythrocyte sedimentation rate
HLA Human leukocyte antigen
MMP Matrix metalloproteinases
NSAIDs Nonsteroidal anti-inflammatory drugs
OCT Optical coherence tomography
OD Right eye (oculus dexter)
OS Left eye (oculus sinister)
RA Rheumatoid arthritis
TIMP Tissue inhibitors of matrix metalloproteinases
VA Visual acuity
Acknowledgements
None.
Authors' contributions
SDN made substantial contributions to the design and conceptualization of the work, analysis and interpretation of data, and substantively revised the manuscript. ID made substantial contributions to the design and conceptualization of the work, acquisition and interpretation of data, and drafted the manuscript. Both authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The datasets used and analyzed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The report of this case has been performed in accordance with the Declaration of Helsinki, and it was approved by the ethics committee of the Emergency County Hospital in Cluj-Napoca, 7688/21.03.2019.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | GENTAMICIN, INDOMETHACIN, METHOTREXATE | DrugsGivenReaction | CC BY | 33663589 | 19,057,396 | 2021-03-04 |
What was the administration route of drug 'GENTAMICIN'? | Controversy of indomethacin eye drops in the treatment of rheumatoid arthritis-induced corneal ulceration: a case report.
BACKGROUND
Perforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA). Addressing a perforated cornea associated with RA is challenging, since its pathogenesis is not fully elucidated. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) were developed to prevent cystoid macular edema following cataract surgery in patients at risk. Their prescription in inflammation of the anterior segment of the eye may induce negative effects on the ocular surface. We bring into focus a corneal perforation in a patient with RA who used indomethacin eye drops to treat corneal ulceration, but responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our aim is to emphasize two issues: the contraindication of topical indomethacin in corneal defects, and the immediate positive impact of topical cyclosporine 0.1% on corneal healing.
METHODS
A 73-year-old Caucasian woman with a 13-year history of RA was treated for corneal ulceration in her oculus sinister (OS) with topical indomethacin and gentamicin. The patient was being treated with systemic immunosuppression and NSAIDs for the underlying RA and artificial tears in both eyes. No bandage contact lens was used. After 3 weeks of treatment, perforation of the left cornea occurred and the patient was referred to our hospital. Upon admission, visual acuity (VA) in the OS was 20/630. Slit lamp examination of the OS revealed paracentral corneal perforation, iris plugging the perforation site, shallow anterior chamber, clear aqueous humor, and clear lens. Anterior segment optical coherence tomography showed the inclavated iris in the perforation site and minimum corneal thickness of 101 µm. Topical NSAIDs were discontinued and topical treatment was initiated with tobramycin, tropicamide 1%, phenylephrine 10%, and artificial tears five times a day, and occlusive patch. For 5 days, there was no improvement, so topical cyclosporine 0.1% was started, one drop every evening. Within 7 days, the cornea had healed, the iris was liberated from the perforation site, the minimum corneal thickness increased to 250 µm, VA improved to 20/25, and the patient was free of symptoms.
CONCLUSIONS
The main "takeaway" lessons from this case are that topical indomethacin should not be prescribed in cases of inflammation of the anterior segment of the eye, and that topical cyclosporine was efficacious in healing corneal perforation in our patient.
Background
Perforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA) [1, 2]. This paper reports the case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin prior to admission to our hospital. Although the pathogenesis of corneal perforation is complex [1, 2], we aim to call attention to the potentially devastating effects of topical indomethacin on the cornea, if not properly indicated [3, 4]. Topical nonsteroidal anti inflammatory drugs (NSAIDs) are designed to prevent cystoid macular edema after cataract surgery in patients at risk, not to treat inflammation of the anterior segment of the eye [3, 4]. Unfortunately, some eye care physicians prescribe them routinely for inflammation of the anterior segment of the eye, with potential side effects, among which corneal perforation is the most severe. We bring into focus a case of corneal perforation in a patient with RA with prolonged use of topical indomethacin, but who responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our case joins a few other reports in the literature related to the occurrence of severe corneal lesions following prolonged topical treatment with NSAIDs, sounding a warning signal on their accurate indication [3, 4]. We also emphasize the immediate positive effect of topical cyclosporine 0.1% on the corneal healing process.
Informed consent was obtained from the patient regarding the publication of this case and the related images.
Case presentation
A 73-year-old Caucasian woman with a 13-year history of RA complained of a marked decrease in visual acuity (VA) and intense pain in her oculus sinister (OS), which was red, accompanied by a sensation of hot leakage on her cheek, approximately 12 hours before admission to our hospital. For the past 3 weeks she had been treated in another service with gentamicin drops and indomethacin drops four times a day for a previously diagnosed corneal ulceration of the OS. No bandage contact lens was used. Before this episode, the patient did not have regular ophthalmological follow-ups. The patient had no history of hypertension or diabetes.
The patient was using methotrexate 2.5 mg three times a week for treatment of RA. For the dry eye syndrome, preservative-free lubricants were prescribed.
Upon ophthalmic examination, visual acuity (VA) was 20/32 in the oculus dexter (OD) and 20/630 in the OS. Slit lamp examination revealed subtle conjunctival congestion with fine stromal opacities in the OD, and in the OS, moderate ciliary injection, a perforated paracentral corneal ulceration approximately 1 mm in diameter, with a dense perilesional infiltrate, stromal melting, and a few corneal new vessels and stromal opacities around it (Fig. 1). The pupil was peaked but reactive and the iris was plugging the perforation. A shallow, almost flat anterior chamber with clear aqueous humor and a clear lens were found (Fig. 1). No abnormality was noted in the fundus examination of the eyes. Anterior segment optical coherence tomography (OCT, Heidelberg Spectralis) revealed the inclavated iris in the ulceration zone and a thin cornea in the OS and an imminent 100 µm minimum corneal thickness at the site of perforation (Fig. 2).Fig. 1 Slit lamp examination: perforated paracentral corneal ulceration, with dense perilesional infiltrate, stromal melting, a few corneal new vessels and stromal opacities, shallow anterior chamber, clear aqueous humor, iris plugging the corneal perforation
Fig. 2 Anterior segment optical coherence tomography (Heidelberg Spectralis): corneal thinning (minimum corneal thickness 101 µm), iris plugging the perforation site
Ophthalmological evaluation led us to the diagnosis of paracentral corneal perforation.
Systemic treatment with Ceftriaxone was initiated, 1 g every 12 hours, and topical medication was modified to tobramycin hourly, mydriasis with tropicamide and phenylephrine five times a day, lubricants, and occlusive patch.
Evolution under treatment was stationary without signs of improvement. Therefore, 5 days after admission, cyclosporine 1 mg/ml was added to the topical treatment and it was administered 1 drop a day in the evening. Treatment with Methotrexate 7.5 mg/week was continued.
The danger of this sight-threatening situation required rheumatologist expertise. Taking into account the lack of general symptoms and the normal values of C reactive protein and ESR, neither pulse therapy with methylprednisolone, nor cyclophosphamide addition were taken into consideration.
Fortunately, visual acuity started to improve to 20/63, the perilesional infiltrate decreased in size and depth, the iris was liberated from the perforation site and the corneal transparency improved (Fig. 3). At discharge, VA in the OS was 20/25 and the patient was free of symptoms.Fig. 3. Slit lamp examination of the left eye 7 days following treatment: corneal perforation sealed, dense perilesional infiltrate, and stromal melting diminished considerably, anterior chamber has normal depth
Anterior segment optical coherence tomography showed an increase in minimum corneal thickness to 250 µm (Fig. 4). We performed a Schirmer test without anesthesia in the OD, and the result was 1 mm at 5 minutes.Fig. 4. Anterior segment optical coherence tomography of the left eye 7 days after treatment (Heidelberg Spectralis): minimum corneal thickness of 250 µm, iris liberated from the perforation site
After having been discharged, the patient continued topical treatment with tobramycin three times/day and cyclosporine 1mg/ml, one drop/day every evening and preservative-free eye lubricants; 6 months after this episode, the patient experienced no further ocular complains, her vision is 20/20 in both eyes, she is under rheumatologic and ophthalmological supervision and keeps using preservative-free ocular lubricants.
Discussion and conclusions
Rheumatoid arthritis (RA), a chronic systemic autoimmune inflammatory entity, is one of the most common collagen vascular diseases. It affects 3–5% of the adult population, more frequently women than men, with an average age at onset of 35–40 years [1]. RA can affect the eye at multiple levels: anterior segment (keratoconjunctivitis sicca, punctate keratopathy, keratitis, episcleritis, scleritis), extraocular muscles, and posterior segment (choroid, retina, optic nerve) [1]. About 90% of patients with RA suffer from dry eye syndrome, especially keratoconjunctivitis sicca, which seems to be correlated with a disease course longer than 10 years [2]. With regard to corneal involvement, many types of keratitis have been described in RA, including peripheral limbal furrow, peripheral or paracentral ulcerative keratitis, keratolysis, acute stromal keratitis, and sclerosing keratitis.
We bring into discussion a case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin, which we managed to treat satisfactorily using a medical approach. Establishing the etiological diagnosis was challenging in this case, and most likely there are several implicating factors: RA definitely plays the main role through modification of the corneal structure and the associated ocular dryness, but the prolonged treatment with topical indomethacin cannot be ruled out, at least at the secondary level.
The pathogenesis of RA-associated corneal ulceration is far from fully elucidated [1]. It seems to be an imbalance between matrix metalloproteinases (MMP) such as MMP-2 in the corneal stroma and MMP-9 in the lacrimal glands and tissue inhibitors of matrix metalloproteinases (TIMP-1) [1, 2, 4]. Reduced levels of TIMP-1 are responsible for high collagenase activity that leads to a keratolytic sterile process [2]. A resulting altered epithelial barrier facilitates the entrance of inflammatory mediators such as monocytes and macrophages in the stroma that subsequently leads to activation of T cells, resulting in production of antibodies and formation of immune complexes. There seems to be significant human leukocyte antigen–DR isotype (HLA-DR) expression by stromal keratocytes and epithelium determined by interferon gamma released by TH2 lymphocytes [1]. Local cytokines such as interleukin-1 and tumor necrosis factor-alpha induce production of collagenase and protease [1, 2, 5, 6]. Paracentral ulcerative keratitis develops in patients with severe dry eye but without marked conjunctival inflammation, such as our case [1, 2].
The initiation of topical cyclosporine therapy was the key to successful treatment given that it arrested the keratolysis and led to ulcer re-epithelialization [7]. There are several reports that recommend topical cyclosporine for corneal ulcer associated with RA [7, 8], as it may enable epithelial healing while reducing cell-mediated immune reactions in the cornea [9]. In our case, topical cyclosporine was initiated with a 5-day delay, as it is expensive and not immediately available. Before the administration of topical cyclosporine, the corneal ulcer did not show significant improvement. Regarding systemic chemotherapy in rheumatoid corneal perforations, there are no clear guidelines, but a strong collaboration between ophthalmologists and rheumatologists is essential to assess the systemic disease status and to determine the need to change or adjust the immunosuppressive therapy.
Although the patient was on immunosuppressive treatment and free of systemic symptoms, she still developed corneal ulceration, highlighting the fact that there are several events initiating corneal lesions and others perpetuating them, such as infection that accelerates corneal melting [5].
The previously diagnosed dry eye syndrome in the context of RA, even under treatment with preservative-free lubricants, favored the ulceration development [8]. There are studies showing that the corneal central thickness and stromal thickness in patients with RA are statistically significantly lower than in controls [1, 2]. Additionally, there is evidence of proteolytic degradation in both corneas of patients ranging from early xerophthalmia to ulcerating xerophthalmia [1, 8].
The use of topical indomethacin in our case is questionable [4, 10]. There have been case reports with patients taking topical NSAIDs who developed corneal perforation that healed after discontinuation [3, 4]. Moreover, it has been shown that topical NSAIDs are associated with corneal hypoesthesia and may be responsible for corneal perforation [3, 4].
Even if the clinical aspect was suggestive of sterile ulcerative keratitis (clear cornea and aqueous), treating the condition exclusively as an autoimmune corneal melt without antibiotic coverage could have resulted in a potentially blinding condition [5]. For logistical reasons we did not have the ability to perform corneal scraping, and therefore we chose topical and systemic treatment with broad-spectrum antibiotics.
Considering the positive outcome following topical cyclosporine, the role of inflammation proved to be essential.
In cases with perforation, the application of cyanoacrylate adhesive, lamellar grafting, or tarsorrhaphy is indicated, depending on ulceration size [1]. In our case, the presence of the iris at the ulceration site acted like a self-adhesive substance.
Nevertheless, photographs of the lesion were helpful in evaluating regression. Anterior segment OCT images were particularly important, highlighting the anatomical improvement.
Corneal perforated ulceration is a rare complication secondary to RA. This case signals and demonstrates that even though the underlying disease was well controlled and monitored, and the dry eye was properly addressed, corneal ulceration still occurred in this RA patient. Indomethacin administered topically may have precipitated corneal perforation, but cyclosporine associated with antibiotics led to good visual outcome. However, since the patient had already been diagnosed with corneal ulcer in another service, there is a possibility that the corneal perforation was a natural course of peripheral ulcerative keratitis (PUK) and undertreatment, rather than due to indomethacin drops. Establishing a cause-effect relationship in this scenario when natural course of the disease is a major confounding factor is difficult and the assumption that indomethacin is the sole culprit here is questionable. Methotrexate 7.5 mg/week is the usual lowest prescribed dose in PUK. Therefore, we can assume that the progression of the ulcer might have been prevented by increasing the methotrexate dose or by adding systemic steroids.
Anterior segment OCT has demonstrated its valuable role in monitoring the disease from a structural perspective.
The main “takeaway” lessons from this case are that topical indomethacin should not be used in corneal ulcers, and that topical cyclosporine was efficacious in healing corneal perforation in a patient with RA.
Abbreviations
ESR Erythrocyte sedimentation rate
HLA Human leukocyte antigen
MMP Matrix metalloproteinases
NSAIDs Nonsteroidal anti-inflammatory drugs
OCT Optical coherence tomography
OD Right eye (oculus dexter)
OS Left eye (oculus sinister)
RA Rheumatoid arthritis
TIMP Tissue inhibitors of matrix metalloproteinases
VA Visual acuity
Acknowledgements
None.
Authors' contributions
SDN made substantial contributions to the design and conceptualization of the work, analysis and interpretation of data, and substantively revised the manuscript. ID made substantial contributions to the design and conceptualization of the work, acquisition and interpretation of data, and drafted the manuscript. Both authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The datasets used and analyzed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The report of this case has been performed in accordance with the Declaration of Helsinki, and it was approved by the ethics committee of the Emergency County Hospital in Cluj-Napoca, 7688/21.03.2019.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Ophthalmic | DrugAdministrationRoute | CC BY | 33663589 | 19,057,090 | 2021-03-04 |
What was the outcome of reaction 'Corneal perforation'? | Controversy of indomethacin eye drops in the treatment of rheumatoid arthritis-induced corneal ulceration: a case report.
BACKGROUND
Perforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA). Addressing a perforated cornea associated with RA is challenging, since its pathogenesis is not fully elucidated. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) were developed to prevent cystoid macular edema following cataract surgery in patients at risk. Their prescription in inflammation of the anterior segment of the eye may induce negative effects on the ocular surface. We bring into focus a corneal perforation in a patient with RA who used indomethacin eye drops to treat corneal ulceration, but responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our aim is to emphasize two issues: the contraindication of topical indomethacin in corneal defects, and the immediate positive impact of topical cyclosporine 0.1% on corneal healing.
METHODS
A 73-year-old Caucasian woman with a 13-year history of RA was treated for corneal ulceration in her oculus sinister (OS) with topical indomethacin and gentamicin. The patient was being treated with systemic immunosuppression and NSAIDs for the underlying RA and artificial tears in both eyes. No bandage contact lens was used. After 3 weeks of treatment, perforation of the left cornea occurred and the patient was referred to our hospital. Upon admission, visual acuity (VA) in the OS was 20/630. Slit lamp examination of the OS revealed paracentral corneal perforation, iris plugging the perforation site, shallow anterior chamber, clear aqueous humor, and clear lens. Anterior segment optical coherence tomography showed the inclavated iris in the perforation site and minimum corneal thickness of 101 µm. Topical NSAIDs were discontinued and topical treatment was initiated with tobramycin, tropicamide 1%, phenylephrine 10%, and artificial tears five times a day, and occlusive patch. For 5 days, there was no improvement, so topical cyclosporine 0.1% was started, one drop every evening. Within 7 days, the cornea had healed, the iris was liberated from the perforation site, the minimum corneal thickness increased to 250 µm, VA improved to 20/25, and the patient was free of symptoms.
CONCLUSIONS
The main "takeaway" lessons from this case are that topical indomethacin should not be prescribed in cases of inflammation of the anterior segment of the eye, and that topical cyclosporine was efficacious in healing corneal perforation in our patient.
Background
Perforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA) [1, 2]. This paper reports the case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin prior to admission to our hospital. Although the pathogenesis of corneal perforation is complex [1, 2], we aim to call attention to the potentially devastating effects of topical indomethacin on the cornea, if not properly indicated [3, 4]. Topical nonsteroidal anti inflammatory drugs (NSAIDs) are designed to prevent cystoid macular edema after cataract surgery in patients at risk, not to treat inflammation of the anterior segment of the eye [3, 4]. Unfortunately, some eye care physicians prescribe them routinely for inflammation of the anterior segment of the eye, with potential side effects, among which corneal perforation is the most severe. We bring into focus a case of corneal perforation in a patient with RA with prolonged use of topical indomethacin, but who responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our case joins a few other reports in the literature related to the occurrence of severe corneal lesions following prolonged topical treatment with NSAIDs, sounding a warning signal on their accurate indication [3, 4]. We also emphasize the immediate positive effect of topical cyclosporine 0.1% on the corneal healing process.
Informed consent was obtained from the patient regarding the publication of this case and the related images.
Case presentation
A 73-year-old Caucasian woman with a 13-year history of RA complained of a marked decrease in visual acuity (VA) and intense pain in her oculus sinister (OS), which was red, accompanied by a sensation of hot leakage on her cheek, approximately 12 hours before admission to our hospital. For the past 3 weeks she had been treated in another service with gentamicin drops and indomethacin drops four times a day for a previously diagnosed corneal ulceration of the OS. No bandage contact lens was used. Before this episode, the patient did not have regular ophthalmological follow-ups. The patient had no history of hypertension or diabetes.
The patient was using methotrexate 2.5 mg three times a week for treatment of RA. For the dry eye syndrome, preservative-free lubricants were prescribed.
Upon ophthalmic examination, visual acuity (VA) was 20/32 in the oculus dexter (OD) and 20/630 in the OS. Slit lamp examination revealed subtle conjunctival congestion with fine stromal opacities in the OD, and in the OS, moderate ciliary injection, a perforated paracentral corneal ulceration approximately 1 mm in diameter, with a dense perilesional infiltrate, stromal melting, and a few corneal new vessels and stromal opacities around it (Fig. 1). The pupil was peaked but reactive and the iris was plugging the perforation. A shallow, almost flat anterior chamber with clear aqueous humor and a clear lens were found (Fig. 1). No abnormality was noted in the fundus examination of the eyes. Anterior segment optical coherence tomography (OCT, Heidelberg Spectralis) revealed the inclavated iris in the ulceration zone and a thin cornea in the OS and an imminent 100 µm minimum corneal thickness at the site of perforation (Fig. 2).Fig. 1 Slit lamp examination: perforated paracentral corneal ulceration, with dense perilesional infiltrate, stromal melting, a few corneal new vessels and stromal opacities, shallow anterior chamber, clear aqueous humor, iris plugging the corneal perforation
Fig. 2 Anterior segment optical coherence tomography (Heidelberg Spectralis): corneal thinning (minimum corneal thickness 101 µm), iris plugging the perforation site
Ophthalmological evaluation led us to the diagnosis of paracentral corneal perforation.
Systemic treatment with Ceftriaxone was initiated, 1 g every 12 hours, and topical medication was modified to tobramycin hourly, mydriasis with tropicamide and phenylephrine five times a day, lubricants, and occlusive patch.
Evolution under treatment was stationary without signs of improvement. Therefore, 5 days after admission, cyclosporine 1 mg/ml was added to the topical treatment and it was administered 1 drop a day in the evening. Treatment with Methotrexate 7.5 mg/week was continued.
The danger of this sight-threatening situation required rheumatologist expertise. Taking into account the lack of general symptoms and the normal values of C reactive protein and ESR, neither pulse therapy with methylprednisolone, nor cyclophosphamide addition were taken into consideration.
Fortunately, visual acuity started to improve to 20/63, the perilesional infiltrate decreased in size and depth, the iris was liberated from the perforation site and the corneal transparency improved (Fig. 3). At discharge, VA in the OS was 20/25 and the patient was free of symptoms.Fig. 3. Slit lamp examination of the left eye 7 days following treatment: corneal perforation sealed, dense perilesional infiltrate, and stromal melting diminished considerably, anterior chamber has normal depth
Anterior segment optical coherence tomography showed an increase in minimum corneal thickness to 250 µm (Fig. 4). We performed a Schirmer test without anesthesia in the OD, and the result was 1 mm at 5 minutes.Fig. 4. Anterior segment optical coherence tomography of the left eye 7 days after treatment (Heidelberg Spectralis): minimum corneal thickness of 250 µm, iris liberated from the perforation site
After having been discharged, the patient continued topical treatment with tobramycin three times/day and cyclosporine 1mg/ml, one drop/day every evening and preservative-free eye lubricants; 6 months after this episode, the patient experienced no further ocular complains, her vision is 20/20 in both eyes, she is under rheumatologic and ophthalmological supervision and keeps using preservative-free ocular lubricants.
Discussion and conclusions
Rheumatoid arthritis (RA), a chronic systemic autoimmune inflammatory entity, is one of the most common collagen vascular diseases. It affects 3–5% of the adult population, more frequently women than men, with an average age at onset of 35–40 years [1]. RA can affect the eye at multiple levels: anterior segment (keratoconjunctivitis sicca, punctate keratopathy, keratitis, episcleritis, scleritis), extraocular muscles, and posterior segment (choroid, retina, optic nerve) [1]. About 90% of patients with RA suffer from dry eye syndrome, especially keratoconjunctivitis sicca, which seems to be correlated with a disease course longer than 10 years [2]. With regard to corneal involvement, many types of keratitis have been described in RA, including peripheral limbal furrow, peripheral or paracentral ulcerative keratitis, keratolysis, acute stromal keratitis, and sclerosing keratitis.
We bring into discussion a case of perforated corneal ulceration in a patient with RA that had been treated for 3 weeks with topical indomethacin, which we managed to treat satisfactorily using a medical approach. Establishing the etiological diagnosis was challenging in this case, and most likely there are several implicating factors: RA definitely plays the main role through modification of the corneal structure and the associated ocular dryness, but the prolonged treatment with topical indomethacin cannot be ruled out, at least at the secondary level.
The pathogenesis of RA-associated corneal ulceration is far from fully elucidated [1]. It seems to be an imbalance between matrix metalloproteinases (MMP) such as MMP-2 in the corneal stroma and MMP-9 in the lacrimal glands and tissue inhibitors of matrix metalloproteinases (TIMP-1) [1, 2, 4]. Reduced levels of TIMP-1 are responsible for high collagenase activity that leads to a keratolytic sterile process [2]. A resulting altered epithelial barrier facilitates the entrance of inflammatory mediators such as monocytes and macrophages in the stroma that subsequently leads to activation of T cells, resulting in production of antibodies and formation of immune complexes. There seems to be significant human leukocyte antigen–DR isotype (HLA-DR) expression by stromal keratocytes and epithelium determined by interferon gamma released by TH2 lymphocytes [1]. Local cytokines such as interleukin-1 and tumor necrosis factor-alpha induce production of collagenase and protease [1, 2, 5, 6]. Paracentral ulcerative keratitis develops in patients with severe dry eye but without marked conjunctival inflammation, such as our case [1, 2].
The initiation of topical cyclosporine therapy was the key to successful treatment given that it arrested the keratolysis and led to ulcer re-epithelialization [7]. There are several reports that recommend topical cyclosporine for corneal ulcer associated with RA [7, 8], as it may enable epithelial healing while reducing cell-mediated immune reactions in the cornea [9]. In our case, topical cyclosporine was initiated with a 5-day delay, as it is expensive and not immediately available. Before the administration of topical cyclosporine, the corneal ulcer did not show significant improvement. Regarding systemic chemotherapy in rheumatoid corneal perforations, there are no clear guidelines, but a strong collaboration between ophthalmologists and rheumatologists is essential to assess the systemic disease status and to determine the need to change or adjust the immunosuppressive therapy.
Although the patient was on immunosuppressive treatment and free of systemic symptoms, she still developed corneal ulceration, highlighting the fact that there are several events initiating corneal lesions and others perpetuating them, such as infection that accelerates corneal melting [5].
The previously diagnosed dry eye syndrome in the context of RA, even under treatment with preservative-free lubricants, favored the ulceration development [8]. There are studies showing that the corneal central thickness and stromal thickness in patients with RA are statistically significantly lower than in controls [1, 2]. Additionally, there is evidence of proteolytic degradation in both corneas of patients ranging from early xerophthalmia to ulcerating xerophthalmia [1, 8].
The use of topical indomethacin in our case is questionable [4, 10]. There have been case reports with patients taking topical NSAIDs who developed corneal perforation that healed after discontinuation [3, 4]. Moreover, it has been shown that topical NSAIDs are associated with corneal hypoesthesia and may be responsible for corneal perforation [3, 4].
Even if the clinical aspect was suggestive of sterile ulcerative keratitis (clear cornea and aqueous), treating the condition exclusively as an autoimmune corneal melt without antibiotic coverage could have resulted in a potentially blinding condition [5]. For logistical reasons we did not have the ability to perform corneal scraping, and therefore we chose topical and systemic treatment with broad-spectrum antibiotics.
Considering the positive outcome following topical cyclosporine, the role of inflammation proved to be essential.
In cases with perforation, the application of cyanoacrylate adhesive, lamellar grafting, or tarsorrhaphy is indicated, depending on ulceration size [1]. In our case, the presence of the iris at the ulceration site acted like a self-adhesive substance.
Nevertheless, photographs of the lesion were helpful in evaluating regression. Anterior segment OCT images were particularly important, highlighting the anatomical improvement.
Corneal perforated ulceration is a rare complication secondary to RA. This case signals and demonstrates that even though the underlying disease was well controlled and monitored, and the dry eye was properly addressed, corneal ulceration still occurred in this RA patient. Indomethacin administered topically may have precipitated corneal perforation, but cyclosporine associated with antibiotics led to good visual outcome. However, since the patient had already been diagnosed with corneal ulcer in another service, there is a possibility that the corneal perforation was a natural course of peripheral ulcerative keratitis (PUK) and undertreatment, rather than due to indomethacin drops. Establishing a cause-effect relationship in this scenario when natural course of the disease is a major confounding factor is difficult and the assumption that indomethacin is the sole culprit here is questionable. Methotrexate 7.5 mg/week is the usual lowest prescribed dose in PUK. Therefore, we can assume that the progression of the ulcer might have been prevented by increasing the methotrexate dose or by adding systemic steroids.
Anterior segment OCT has demonstrated its valuable role in monitoring the disease from a structural perspective.
The main “takeaway” lessons from this case are that topical indomethacin should not be used in corneal ulcers, and that topical cyclosporine was efficacious in healing corneal perforation in a patient with RA.
Abbreviations
ESR Erythrocyte sedimentation rate
HLA Human leukocyte antigen
MMP Matrix metalloproteinases
NSAIDs Nonsteroidal anti-inflammatory drugs
OCT Optical coherence tomography
OD Right eye (oculus dexter)
OS Left eye (oculus sinister)
RA Rheumatoid arthritis
TIMP Tissue inhibitors of matrix metalloproteinases
VA Visual acuity
Acknowledgements
None.
Authors' contributions
SDN made substantial contributions to the design and conceptualization of the work, analysis and interpretation of data, and substantively revised the manuscript. ID made substantial contributions to the design and conceptualization of the work, acquisition and interpretation of data, and drafted the manuscript. Both authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The datasets used and analyzed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The report of this case has been performed in accordance with the Declaration of Helsinki, and it was approved by the ethics committee of the Emergency County Hospital in Cluj-Napoca, 7688/21.03.2019.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33663589 | 19,057,090 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Spontaneously conceived 17-week heterotopic pregnancy: a challenging and unusual diagnosis.
A 37-year-old woman, gravida 2 para 1, arrived in our emergency clinic at 16 2/7 weeks of a spontaneously conceived pregnancy for abdominal pain. She was on oral antibiotics for 2 days to treat a suspected urinary tract infection with no improvement. Blood tests, abdominal ultrasound and intrauterine fetus were all normal. She left our emergency unit with laxatives. Four days later, she returned to our clinic with severe abdominal pain. We repeated abdominal and foetal ultrasonography and identified a left para-uterine 7×5 cm mass. As adnexal torsion was suspected, we performed an emergency laparoscopy. At laparoscopy, we found a left haematosalpinx and realised a left salpingectomy. Histology confirmed the presence of a heterotopic pregnancy (HP). This case illustrates the importance of exploring the adnexa in a gravid woman presenting with abdominal pain in the first and early second trimesters. Although rare, excluding a HP may prevent a life-threatening haemorrhage.
Background
First described in 1761 as an autopsy finding,1 heterotopic pregnancy (HP) is defined as concomitant pregnancies developing at two different implantation sites. Most often, an intrauterine pregnancy is seen with a tubal ectopic pregnancy. However, other implantations sites have been described.2 Long considered to be a rare event accounting for 1/30 000 spontaneous pregnancies,3 the incidence of HP has increased with the use of assisted reproductive procedures, reaching rates of 1/100 in this population.4 We report a case of spontaneous HP diagnosed at 17 weeks of amenorrhoea, treated by laparoscopy and followed by the normal development of the intrauterine pregnancy.
Case presentation
A 37-years-old pregnant woman, gravida 2 para 1, consulted our emergency clinic at 16 2/7 weeks of amenorrhoea for abdominal pain, which started 2 days before. Her pregnancy was spontaneously conceived. She was initially treated with cefuroxime prescribed by her gynaecologist who suspected cystitis, but failed to improve. In our service, she had problem of acute left pelvic pain irradiating to the back and left thigh. The patient denied having had vaginal bleeding, urinary or digestive symptoms. She did not have any relevant medical history, except for a normal vaginal delivery 16 months earlier.
On clinical examination, her heart rate was 84 beats/min, blood pressure was 100/55 mm Hg with a temperature of 37.3°C. The abdominal wall was tender without guarding nor rebound. On pelvic examination, there was a small quantity of blood in the vagina, and no adnexal mass was palpable on bimanual examination. The uterus was measured at 17 cm, as expected for the gestational age.
Investigations
In order to exclude a urinary tract infection, we performed a blood analysis and a urine dipstick/culture. Both examinations were normal (red blood cell count of 114 g/L, white cell count of 6.6×109/L, C reactive protein 12.7 mg/L, creatinine 47 µmol/L). Nephrolithiasis and appendicitis were ruled out by an abdominal ultrasonography. Obstetrical ultrasonography showed a viable fetus corresponding to the weeks of amenorrhoea. However, the adnexa were not described initially. The patient left our emergency unit with laxatives for suspected constipation.
Four days later, she returned to our emergency unit with severe abdominal pain. At clinical examination, she had signs of peritoneal irritation. We repeated laboratory exams. Blood test revealed a decrease in the haemoglobin value (101 g/L vs 114 g/L). White cell blood count was stable. Ultrasonography showed an ongoing intrauterine pregnancy, but also a poorly vascularised left para-uterine 7×5 cm mass (figure 1) sensitive to probe passage.
Figure 1 Left para-uterine mass 7×5 cm.
Differential diagnosis
Based on the ultrasonography, we suspected a possible adnexal torsion or haemorrhagic rupture of an ovarian cyst. Non-gynaecological causes such as appendicitis, constipation or urinary tract disorders (infection, lithiasis) were less likely. There was no visible myoma to suspect necrobiosis.
Treatment
To exclude a potential life-threatening condition, we performed an emergency laparoscopy. To avoid haemodynamic and respiratory adverse effects on placental blood flow,5 we insufflated the gaz (CO2) in the left hypochondrium using low pneumoperitoneum pressure (less than 12 mm Hg). The intraoperative status revealed a 100 mL haemoperitoneum and a complex left adnexal mass of 5×7 cm (figures 2 and 3) adherent to the uterus and surrounded by clots. After careful adhesiolysis, we performed a left salpingectomy for suspicion of tubal HP.
Figure 2 Left adnexal mass surrounded by a haematoma.
Figure 3 Left tubal heterotopic pregnancy.
Outcome and follow-up
Histology confirmed the presence of chorionic villus. The postoperative course was uneventful. Two days after surgery, ultrasound confirmed the well-being of the intrauterine fetus. The patient was discharged on the third postoperative day.
Later on, at 40 3/7 weeks, she delivered a healthy live baby by caesarean after induction of labour for post-term pregnancy had failed.
Discussion
Most publications report HP in the second trimester after assisted reproductive therapy. This condition occurs very rarely in spontaneous pregnancy.6–8. In our case report, the failure to identify this condition and evaluate the adnexa during initial care could have resulted in a disastrous outcome.
Apart from assisted reproductive procedures,9 risk factors for HP are pelvic inflammatory disease, history of ectopic pregnancy and/or pelvic surgery.2 In a systematic review,2 HP occurred in 29% of women without any risk factors, as was the case in our patient, resulting in delayed diagnosis and treatment. Symptoms such as abdominal pain, vaginal bleeding or signs of haemodynamic instability can be present, but are not always the case.2 In a retrospective study, 32% of patients remained asymptomatic at diagnosis.10
Serum beta-hCG assay is not useful in the diagnosis of HP.9 Transvaginal ultrasonography is a diagnostic tool with a sensitivity of 92% and specificity of 100% in a population where HP is actively sought.9 The sensitivity rate is drastically reduced to 66%, if HP was not previously suspected.2
It is therefore important to exclude an HP in every gravid woman presenting with abdominal pain in the first and early second trimester. Accurate diagnosis is of utmost importance as it promotes adequate treatment to prevent complications of tubal rupture. This could not only lead to life-threatening haemorrhage, but also to spontaneous abortion of the intrauterine pregnancy, reported in 12%–26% of HP.2 10
Therapeutic options are most often surgical, either by laparoscopy or by laparotomy. According to the Talbot et al review,2 33% of patients are haemodynamically unstable, making laparotomy mandatory. If the patient is haemodynamically stable, the laparoscopic approach is preferred if performed by an experienced surgeon.11 During surgery, the ectopic pregnancy is removed while efforts are made to preserve the intrauterine pregnancy. For laparoscopy, use of low pneumoperitoneum pressure is required, after needle insertion distant from the gravid uterus.5 Medical treatment is preferred in cases of interstitial,12 cervical13 and caesarean scar heterotopic pregnancy.14 In these situations, drugs such as potassium chloride, methotrexate or hyperosmolar glucose are administered under ultrasonographic visualisation into the extrauterine gestational sac.
In conclusion, HP is a diagnostic and therapeutic challenge. Adequate and timely approach can not only prevent a life-threatening tubal rupture, but also miscarriage of a concomitant intrauterine pregnancy. It is therefore important to consider this diagnosis in every gravid woman presenting with abdominal pain in the first half of pregnancy. Evaluation of the adnexa using abdominal and transvaginal ultrasonography should always be performed.
Learning points
Symptoms of chronic heterotopic pregnancy may be mild and mimic other abdominal pathologies thus delaying diagnosis.
Heterotopic ectopic pregnancy should be considered in the differential diagnosis of pregnant women with abdominal pain.
In order to exclude this condition, evaluation of the adnexa using abdominal and transvaginal ultrasonography should always be performed during the first half of pregnancy.
Contributors: SdO: authorship, acquisition of data, review of the literature, interpretation of the case. PD: authorship, acquisition of data, interpretation of the case. MY: authorship, review of the case.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | CEFUROXIME | DrugsGivenReaction | CC BY-NC | 33664020 | 19,930,459 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normal newborn'. | Spontaneously conceived 17-week heterotopic pregnancy: a challenging and unusual diagnosis.
A 37-year-old woman, gravida 2 para 1, arrived in our emergency clinic at 16 2/7 weeks of a spontaneously conceived pregnancy for abdominal pain. She was on oral antibiotics for 2 days to treat a suspected urinary tract infection with no improvement. Blood tests, abdominal ultrasound and intrauterine fetus were all normal. She left our emergency unit with laxatives. Four days later, she returned to our clinic with severe abdominal pain. We repeated abdominal and foetal ultrasonography and identified a left para-uterine 7×5 cm mass. As adnexal torsion was suspected, we performed an emergency laparoscopy. At laparoscopy, we found a left haematosalpinx and realised a left salpingectomy. Histology confirmed the presence of a heterotopic pregnancy (HP). This case illustrates the importance of exploring the adnexa in a gravid woman presenting with abdominal pain in the first and early second trimesters. Although rare, excluding a HP may prevent a life-threatening haemorrhage.
Background
First described in 1761 as an autopsy finding,1 heterotopic pregnancy (HP) is defined as concomitant pregnancies developing at two different implantation sites. Most often, an intrauterine pregnancy is seen with a tubal ectopic pregnancy. However, other implantations sites have been described.2 Long considered to be a rare event accounting for 1/30 000 spontaneous pregnancies,3 the incidence of HP has increased with the use of assisted reproductive procedures, reaching rates of 1/100 in this population.4 We report a case of spontaneous HP diagnosed at 17 weeks of amenorrhoea, treated by laparoscopy and followed by the normal development of the intrauterine pregnancy.
Case presentation
A 37-years-old pregnant woman, gravida 2 para 1, consulted our emergency clinic at 16 2/7 weeks of amenorrhoea for abdominal pain, which started 2 days before. Her pregnancy was spontaneously conceived. She was initially treated with cefuroxime prescribed by her gynaecologist who suspected cystitis, but failed to improve. In our service, she had problem of acute left pelvic pain irradiating to the back and left thigh. The patient denied having had vaginal bleeding, urinary or digestive symptoms. She did not have any relevant medical history, except for a normal vaginal delivery 16 months earlier.
On clinical examination, her heart rate was 84 beats/min, blood pressure was 100/55 mm Hg with a temperature of 37.3°C. The abdominal wall was tender without guarding nor rebound. On pelvic examination, there was a small quantity of blood in the vagina, and no adnexal mass was palpable on bimanual examination. The uterus was measured at 17 cm, as expected for the gestational age.
Investigations
In order to exclude a urinary tract infection, we performed a blood analysis and a urine dipstick/culture. Both examinations were normal (red blood cell count of 114 g/L, white cell count of 6.6×109/L, C reactive protein 12.7 mg/L, creatinine 47 µmol/L). Nephrolithiasis and appendicitis were ruled out by an abdominal ultrasonography. Obstetrical ultrasonography showed a viable fetus corresponding to the weeks of amenorrhoea. However, the adnexa were not described initially. The patient left our emergency unit with laxatives for suspected constipation.
Four days later, she returned to our emergency unit with severe abdominal pain. At clinical examination, she had signs of peritoneal irritation. We repeated laboratory exams. Blood test revealed a decrease in the haemoglobin value (101 g/L vs 114 g/L). White cell blood count was stable. Ultrasonography showed an ongoing intrauterine pregnancy, but also a poorly vascularised left para-uterine 7×5 cm mass (figure 1) sensitive to probe passage.
Figure 1 Left para-uterine mass 7×5 cm.
Differential diagnosis
Based on the ultrasonography, we suspected a possible adnexal torsion or haemorrhagic rupture of an ovarian cyst. Non-gynaecological causes such as appendicitis, constipation or urinary tract disorders (infection, lithiasis) were less likely. There was no visible myoma to suspect necrobiosis.
Treatment
To exclude a potential life-threatening condition, we performed an emergency laparoscopy. To avoid haemodynamic and respiratory adverse effects on placental blood flow,5 we insufflated the gaz (CO2) in the left hypochondrium using low pneumoperitoneum pressure (less than 12 mm Hg). The intraoperative status revealed a 100 mL haemoperitoneum and a complex left adnexal mass of 5×7 cm (figures 2 and 3) adherent to the uterus and surrounded by clots. After careful adhesiolysis, we performed a left salpingectomy for suspicion of tubal HP.
Figure 2 Left adnexal mass surrounded by a haematoma.
Figure 3 Left tubal heterotopic pregnancy.
Outcome and follow-up
Histology confirmed the presence of chorionic villus. The postoperative course was uneventful. Two days after surgery, ultrasound confirmed the well-being of the intrauterine fetus. The patient was discharged on the third postoperative day.
Later on, at 40 3/7 weeks, she delivered a healthy live baby by caesarean after induction of labour for post-term pregnancy had failed.
Discussion
Most publications report HP in the second trimester after assisted reproductive therapy. This condition occurs very rarely in spontaneous pregnancy.6–8. In our case report, the failure to identify this condition and evaluate the adnexa during initial care could have resulted in a disastrous outcome.
Apart from assisted reproductive procedures,9 risk factors for HP are pelvic inflammatory disease, history of ectopic pregnancy and/or pelvic surgery.2 In a systematic review,2 HP occurred in 29% of women without any risk factors, as was the case in our patient, resulting in delayed diagnosis and treatment. Symptoms such as abdominal pain, vaginal bleeding or signs of haemodynamic instability can be present, but are not always the case.2 In a retrospective study, 32% of patients remained asymptomatic at diagnosis.10
Serum beta-hCG assay is not useful in the diagnosis of HP.9 Transvaginal ultrasonography is a diagnostic tool with a sensitivity of 92% and specificity of 100% in a population where HP is actively sought.9 The sensitivity rate is drastically reduced to 66%, if HP was not previously suspected.2
It is therefore important to exclude an HP in every gravid woman presenting with abdominal pain in the first and early second trimester. Accurate diagnosis is of utmost importance as it promotes adequate treatment to prevent complications of tubal rupture. This could not only lead to life-threatening haemorrhage, but also to spontaneous abortion of the intrauterine pregnancy, reported in 12%–26% of HP.2 10
Therapeutic options are most often surgical, either by laparoscopy or by laparotomy. According to the Talbot et al review,2 33% of patients are haemodynamically unstable, making laparotomy mandatory. If the patient is haemodynamically stable, the laparoscopic approach is preferred if performed by an experienced surgeon.11 During surgery, the ectopic pregnancy is removed while efforts are made to preserve the intrauterine pregnancy. For laparoscopy, use of low pneumoperitoneum pressure is required, after needle insertion distant from the gravid uterus.5 Medical treatment is preferred in cases of interstitial,12 cervical13 and caesarean scar heterotopic pregnancy.14 In these situations, drugs such as potassium chloride, methotrexate or hyperosmolar glucose are administered under ultrasonographic visualisation into the extrauterine gestational sac.
In conclusion, HP is a diagnostic and therapeutic challenge. Adequate and timely approach can not only prevent a life-threatening tubal rupture, but also miscarriage of a concomitant intrauterine pregnancy. It is therefore important to consider this diagnosis in every gravid woman presenting with abdominal pain in the first half of pregnancy. Evaluation of the adnexa using abdominal and transvaginal ultrasonography should always be performed.
Learning points
Symptoms of chronic heterotopic pregnancy may be mild and mimic other abdominal pathologies thus delaying diagnosis.
Heterotopic ectopic pregnancy should be considered in the differential diagnosis of pregnant women with abdominal pain.
In order to exclude this condition, evaluation of the adnexa using abdominal and transvaginal ultrasonography should always be performed during the first half of pregnancy.
Contributors: SdO: authorship, acquisition of data, review of the literature, interpretation of the case. PD: authorship, acquisition of data, interpretation of the case. MY: authorship, review of the case.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | CEFUROXIME | DrugsGivenReaction | CC BY-NC | 33664020 | 19,930,459 | 2021-03-04 |
What was the administration route of drug 'CEFUROXIME'? | Spontaneously conceived 17-week heterotopic pregnancy: a challenging and unusual diagnosis.
A 37-year-old woman, gravida 2 para 1, arrived in our emergency clinic at 16 2/7 weeks of a spontaneously conceived pregnancy for abdominal pain. She was on oral antibiotics for 2 days to treat a suspected urinary tract infection with no improvement. Blood tests, abdominal ultrasound and intrauterine fetus were all normal. She left our emergency unit with laxatives. Four days later, she returned to our clinic with severe abdominal pain. We repeated abdominal and foetal ultrasonography and identified a left para-uterine 7×5 cm mass. As adnexal torsion was suspected, we performed an emergency laparoscopy. At laparoscopy, we found a left haematosalpinx and realised a left salpingectomy. Histology confirmed the presence of a heterotopic pregnancy (HP). This case illustrates the importance of exploring the adnexa in a gravid woman presenting with abdominal pain in the first and early second trimesters. Although rare, excluding a HP may prevent a life-threatening haemorrhage.
Background
First described in 1761 as an autopsy finding,1 heterotopic pregnancy (HP) is defined as concomitant pregnancies developing at two different implantation sites. Most often, an intrauterine pregnancy is seen with a tubal ectopic pregnancy. However, other implantations sites have been described.2 Long considered to be a rare event accounting for 1/30 000 spontaneous pregnancies,3 the incidence of HP has increased with the use of assisted reproductive procedures, reaching rates of 1/100 in this population.4 We report a case of spontaneous HP diagnosed at 17 weeks of amenorrhoea, treated by laparoscopy and followed by the normal development of the intrauterine pregnancy.
Case presentation
A 37-years-old pregnant woman, gravida 2 para 1, consulted our emergency clinic at 16 2/7 weeks of amenorrhoea for abdominal pain, which started 2 days before. Her pregnancy was spontaneously conceived. She was initially treated with cefuroxime prescribed by her gynaecologist who suspected cystitis, but failed to improve. In our service, she had problem of acute left pelvic pain irradiating to the back and left thigh. The patient denied having had vaginal bleeding, urinary or digestive symptoms. She did not have any relevant medical history, except for a normal vaginal delivery 16 months earlier.
On clinical examination, her heart rate was 84 beats/min, blood pressure was 100/55 mm Hg with a temperature of 37.3°C. The abdominal wall was tender without guarding nor rebound. On pelvic examination, there was a small quantity of blood in the vagina, and no adnexal mass was palpable on bimanual examination. The uterus was measured at 17 cm, as expected for the gestational age.
Investigations
In order to exclude a urinary tract infection, we performed a blood analysis and a urine dipstick/culture. Both examinations were normal (red blood cell count of 114 g/L, white cell count of 6.6×109/L, C reactive protein 12.7 mg/L, creatinine 47 µmol/L). Nephrolithiasis and appendicitis were ruled out by an abdominal ultrasonography. Obstetrical ultrasonography showed a viable fetus corresponding to the weeks of amenorrhoea. However, the adnexa were not described initially. The patient left our emergency unit with laxatives for suspected constipation.
Four days later, she returned to our emergency unit with severe abdominal pain. At clinical examination, she had signs of peritoneal irritation. We repeated laboratory exams. Blood test revealed a decrease in the haemoglobin value (101 g/L vs 114 g/L). White cell blood count was stable. Ultrasonography showed an ongoing intrauterine pregnancy, but also a poorly vascularised left para-uterine 7×5 cm mass (figure 1) sensitive to probe passage.
Figure 1 Left para-uterine mass 7×5 cm.
Differential diagnosis
Based on the ultrasonography, we suspected a possible adnexal torsion or haemorrhagic rupture of an ovarian cyst. Non-gynaecological causes such as appendicitis, constipation or urinary tract disorders (infection, lithiasis) were less likely. There was no visible myoma to suspect necrobiosis.
Treatment
To exclude a potential life-threatening condition, we performed an emergency laparoscopy. To avoid haemodynamic and respiratory adverse effects on placental blood flow,5 we insufflated the gaz (CO2) in the left hypochondrium using low pneumoperitoneum pressure (less than 12 mm Hg). The intraoperative status revealed a 100 mL haemoperitoneum and a complex left adnexal mass of 5×7 cm (figures 2 and 3) adherent to the uterus and surrounded by clots. After careful adhesiolysis, we performed a left salpingectomy for suspicion of tubal HP.
Figure 2 Left adnexal mass surrounded by a haematoma.
Figure 3 Left tubal heterotopic pregnancy.
Outcome and follow-up
Histology confirmed the presence of chorionic villus. The postoperative course was uneventful. Two days after surgery, ultrasound confirmed the well-being of the intrauterine fetus. The patient was discharged on the third postoperative day.
Later on, at 40 3/7 weeks, she delivered a healthy live baby by caesarean after induction of labour for post-term pregnancy had failed.
Discussion
Most publications report HP in the second trimester after assisted reproductive therapy. This condition occurs very rarely in spontaneous pregnancy.6–8. In our case report, the failure to identify this condition and evaluate the adnexa during initial care could have resulted in a disastrous outcome.
Apart from assisted reproductive procedures,9 risk factors for HP are pelvic inflammatory disease, history of ectopic pregnancy and/or pelvic surgery.2 In a systematic review,2 HP occurred in 29% of women without any risk factors, as was the case in our patient, resulting in delayed diagnosis and treatment. Symptoms such as abdominal pain, vaginal bleeding or signs of haemodynamic instability can be present, but are not always the case.2 In a retrospective study, 32% of patients remained asymptomatic at diagnosis.10
Serum beta-hCG assay is not useful in the diagnosis of HP.9 Transvaginal ultrasonography is a diagnostic tool with a sensitivity of 92% and specificity of 100% in a population where HP is actively sought.9 The sensitivity rate is drastically reduced to 66%, if HP was not previously suspected.2
It is therefore important to exclude an HP in every gravid woman presenting with abdominal pain in the first and early second trimester. Accurate diagnosis is of utmost importance as it promotes adequate treatment to prevent complications of tubal rupture. This could not only lead to life-threatening haemorrhage, but also to spontaneous abortion of the intrauterine pregnancy, reported in 12%–26% of HP.2 10
Therapeutic options are most often surgical, either by laparoscopy or by laparotomy. According to the Talbot et al review,2 33% of patients are haemodynamically unstable, making laparotomy mandatory. If the patient is haemodynamically stable, the laparoscopic approach is preferred if performed by an experienced surgeon.11 During surgery, the ectopic pregnancy is removed while efforts are made to preserve the intrauterine pregnancy. For laparoscopy, use of low pneumoperitoneum pressure is required, after needle insertion distant from the gravid uterus.5 Medical treatment is preferred in cases of interstitial,12 cervical13 and caesarean scar heterotopic pregnancy.14 In these situations, drugs such as potassium chloride, methotrexate or hyperosmolar glucose are administered under ultrasonographic visualisation into the extrauterine gestational sac.
In conclusion, HP is a diagnostic and therapeutic challenge. Adequate and timely approach can not only prevent a life-threatening tubal rupture, but also miscarriage of a concomitant intrauterine pregnancy. It is therefore important to consider this diagnosis in every gravid woman presenting with abdominal pain in the first half of pregnancy. Evaluation of the adnexa using abdominal and transvaginal ultrasonography should always be performed.
Learning points
Symptoms of chronic heterotopic pregnancy may be mild and mimic other abdominal pathologies thus delaying diagnosis.
Heterotopic ectopic pregnancy should be considered in the differential diagnosis of pregnant women with abdominal pain.
In order to exclude this condition, evaluation of the adnexa using abdominal and transvaginal ultrasonography should always be performed during the first half of pregnancy.
Contributors: SdO: authorship, acquisition of data, review of the literature, interpretation of the case. PD: authorship, acquisition of data, interpretation of the case. MY: authorship, review of the case.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33664020 | 19,930,459 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breast tenderness'. | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | ASCORBIC ACID, CHOLECALCIFEROL, ENZALUTAMIDE, HERBALS\TURMERIC, NAPROXEN, POTASSIUM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dizziness'. | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | ASCORBIC ACID, CHOLECALCIFEROL, ENZALUTAMIDE, HERBALS\TURMERIC, NAPROXEN, POTASSIUM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | ASCORBIC ACID, CHOLECALCIFEROL, ENZALUTAMIDE, HERBALS\TURMERIC, NAPROXEN, POTASSIUM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | ASCORBIC ACID, CHOLECALCIFEROL, ENZALUTAMIDE, HERBALS\TURMERIC, NAPROXEN, POTASSIUM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | ASCORBIC ACID, CHOLECALCIFEROL, ENZALUTAMIDE, HERBALS\TURMERIC, NAPROXEN, POTASSIUM, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
What was the administration route of drug 'ENZALUTAMIDE'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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 | 33664086 | 19,174,002 | 2021-03 |
What was the dosage of drug 'ASCORBIC ACID'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | UNK UNK, UNKNOWN FREQ. | DrugDosageText | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
What was the dosage of drug 'ENZALUTAMIDE'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | 160 mg (milligrams). | DrugDosage | CC BY-NC | 33664086 | 19,174,002 | 2021-03 |
What was the outcome of reaction 'Alanine aminotransferase increased'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | Recovering | ReactionOutcome | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
What was the outcome of reaction 'Aspartate aminotransferase increased'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | Recovering | ReactionOutcome | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
What was the outcome of reaction 'Breast tenderness'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | Not recovered | ReactionOutcome | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
What was the outcome of reaction 'Dizziness'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | Not recovered | ReactionOutcome | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
What was the outcome of reaction 'Fatigue'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | Not recovered | ReactionOutcome | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
What was the outcome of reaction 'Nausea'? | Clinical and immunologic impact of short-course enzalutamide alone and with immunotherapy in non-metastatic castration sensitive prostate cancer.
The standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.
Patients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.
Thirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84-1246) and 189 days (78-400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.
Three months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed. TRAIL REGISTRATION NUMBER: clinicaltrials.gov (NCT01875250).
Background
Enzalutamide is an androgen receptor inhibitor that initially demonstrated efficacy in patients with metastatic castration resistant prostate cancer (mCRPC).1 2 In recent years, trials in earlier stages of prostate cancer including metastatic castration sensitive prostate cancer (mCSPC) and non-mCSPC (nmCSPC) have demonstrated the clinical benefit of using enzalutamide before the development of mCRPC.3 4 Another subpopulation worthy of investigation are those with a rising prostate-specific antigen (PSA) after definitive surgery or radiation, but without evidence of metastatic disease on conventional imaging (CT/MRI and Tc99 bone scan).
Approximately 25 000 men in the USA develop nmCSPC annually, also commonly referred to as biochemically recurrent prostate cancer. Standard treatment includes observation until metastatic disease or androgen-deprivation therapy (ADT) based on patient preference or PSA doubling time (PSA DT).5–7 Retrospective data suggest that PSA DT can be used to identify patients who are at highest risk for metastatic disease.8 9 There is also retrospective data suggesting that altering the PSA DT/PSA velocity could impact survival in nmCSPC, but prospective trials are required.10
A single previous study that is published explored the use of indefinite enzalutamide without ADT in nmCSPC and presented efficacy data and toxicities after 25 weeks.11 While these findings are important, efforts should be made to develop strategies to minimize toxicity in an asymptomatic population like nmCSPC. Another trial has demonstrated that intermittent ADT is equivalent to continuous ADT in nmCSPC.12
Based on that data and preclinical data suggesting the potential synergy of enzalutamide with immunotherapy, we conducted a randomized trial of a 3-month course of enzalutamide with and without PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA.13 14 Although PROSTVAC was not effective as a single agent to extend survival in mCRPC, data suggest that it can be synergistic with enzalutamide and perhaps slow tumor growth rates, which would be especially important in nmCSPC.14–16 Immune monitoring was also conducted to evaluate the immunologic impact of enzalutamide and the combination of enzalutamide and PROSTVAC in this population.
Methods
This was a single institution trial conducted at the National Cancer Institute, NIH, Bethesda, Maryland, USA. Patients enrolled from July 2013 to June 2015 (online supplemental figure 1).
10.1136/jitc-2020-001556.supp2 Supplementary data
Eligible patients were required to have had previous definitive therapy with either radiation or surgery. Patients were required to have negative CT scans/MRI and Tc99 bone scans. The eligible PSA range was between 2.0 and 20.0 ng/mL with a PSA DT of less than 12 months. Because of the use of PROSTVAC, patients with autoimmune diseases and requirements for chronic steroids were excluded. Patients who had previous chemotherapy were also excepted. Herbal medications and other medications known to influence PSA were prohibited. Previous ADT was allowed in patients with a normal range testosterone at study entry.
All patients were treated with enzalutamide 160 mg orally (in the absence of ADT) for 84 days. Patients randomized to the vaccine arm were also given PROSTVAC-V (vaccinia, 2×108 infectious units subcutaneous) at week 1, followed by PROSTVAC-F (fowlpox 1×109 infectious units) at weeks 3, 5, 9, 13, 17 and 21. Per protocol, patients were then followed every 4–6 weeks to track PSA recovery to their respective baseline value. After an amendment to the study protocol, patients could have a second 84-day course of enzalutamide if the PSA recovery to baseline was beyond 7 months from treatment initiation and the CT and Tc99 bone scan remained negative for metastatic disease. (No further vaccine was administered.) Thereafter patients were followed until PSA recovery to baseline.
Analysis of antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cell responses against PSA were analyzed in cryopreserved peripheral blood mononuclear cells (PBMCs) collected from patients before and during therapy, by intracellular cytokine staining following a period of in vitro stimulation with overlapping peptides pools using methods previously described.17 The PSA peptide pools contained a previously identified agonist epitope, and peptide pools encoding human leukocyte antigen and a mixture of peptides of cytomegalovirus, Epstein-Barr virus, influenza, and tetanus toxin served as negative and positive controls, respectively.18
Cryopreserved PBMCs collected from patients before and during therapy were examined by multicolor flow cytometry to identify 123 peripheral immune cell subsets, using the methodology previously described.19 20 Subsets evaluated included nine parental cell types (CD4+ and CD8+ T cells, T-regulatory cells, natural killer (NK) cells, NK-T cells, conventional dendritic cells, plasmacytoid dendritic cells, B cells, and myeloid-derived suppressor cells (MDSCs)) and 114 refined subsets related to the maturation/function of the parental cell types. Flow cytometry files were analyzed using FlowJo V9.7 for Macintosh using the outlined gating strategy (online supplemental figure 2) with non-viable cells excluded and negative gates based on fluorescence minus 1 controls. The frequency of all subsets was calculated as a percentage of PBMC to help eliminate the bias that could occur in the smaller populations with fluctuations in leukocyte subpopulations. Immune subsets with a potentially biologically relevant change following therapy were defined as those with p<0.05, the majority of patients having a>25% change, difference in medians >0.05% of PBMCs, and a frequency >0.01% of total PBMCs. Multiple prior studies have used this method to detect the dynamics of 123 immune subsets, many of which have known biologic functions.21–24
10.1136/jitc-2020-001556.supp3 Supplementary data
T cell receptor excision circles (TRECs), a byproduct formed during T cell receptor rearrangement, which identifies recent thymic emigrants, was analyzed on DNA extracted from PBMC, using methods previously described.25 26
Impact of enzalutamide on vascular endothelial growth factor
Preliminary data have suggested that enzalutamide could potentially impact vascular endothelial growth factor (VEGF) and this study involving enzalutamide without ADT provided an opportunity to evaluate that, independent of the immune analysis.27 28 Venous blood was obtained by uncomplicated venipuncture into an EDTA tube at baseline, 4 weeks, 12 weeks and pre and post second course of enzalutamide. Samples were immediately placed on ice and processed within 2 hours of collection. Blood was centrifuged for 5 min at 1200 g and plasma stored at −80 Celsius until time of analysis. VEGF concentrations were measured by a commercial ELISA assay (R&D Systems Quantikine Human VEGF Immunoassay), following manufacturer’s instructions. All samples were evaluated in duplicate and an internal control was included in each plate. The lower limit of quantitation of the assay was 9.0 pg/mL.
Statistical design
The study was designed to evaluate if PROSTVAC could slow the PSA growth rate after a short-course of enzalutamide. The primary endpoint of the trial was to compare the PSA recovery kinetics at 7 months after enzalutamide initiation between the two arms of the study based on previous data suggesting that vaccines could slow tumor growth rate over time.29 30 This was based on retrospective data that suggested vaccines may slow the growth rates in prostate cancer as measured by PSA. With 17 patients in each arm, there would be 80% power to detect a 1 SD difference between the two groups with a two-tailed 0.05 significance level two-group t-test. Up to 38 total patients were allowed to be enrolled, in case a small number of patients were found to be inevaluable. The growth rate was measured via the equation f(t)=exp(-d * t)+exp(g * t)–1, where exp is the base of the natural logarithm, e=2.7182 and t is days since treatment initiation, as previously described.16 Secondary objectives included safety, impact of short-course enzalutamide on PSA kinetics, changes in testosterone, and VEGF levels.
Results
The two groups (n=38) were relatively balanced at enrollment (table 1). The growth rate as measured via the prespecified equation was not different between the two groups (0.031 for enzalutamide alone vs 0.030 for the combination; p=0.74 by Wilcoxon rank sum test) after 7 months (figure 1).
Table 1 Baseline characteristics
Enzalutamide+PROSTVAC Enzalutamide All Patients
Number of Patients 19 19 38
Median Age (Range) 64.4 years (56–79) 68 years (54–87) 64.6 (54–87)
Gleason
6 1 5 6
7 9 6 15
8–10 9 8 17
Median PSA (Range) 3.94 ng/dL (2.02–19.43) 4.49 ng/dL (2.25–16.75) 4.38 ng/dL (2.02–19.43)
Median PSA Doubling Time (Range) 3.3 months (0.9–7.8) 5.2 months (1.6–10.3) 4.1 months (0.9–10.3)
Median Testosterone (Range) 314 ng/dL (182-472) 317 ng/dL (167-723) 316 ng/dL (167-723)
Previous ADT (Percent) 7 (37%) 7 (37%) 14 (37%)
Figure 1 PSA Growth Rates. There was no difference seen in PSA growth rates in the 4 months following enzalutamide discontinuation regardless of the 6-month course of PROSTVAC administered to the combination group. Growth rates defined as previously described.16
Although the trial’s primary endpoint was not met, the impact of the short-course of enzalutamide in all patients, regardless of PROSTVAC, is noteworthy. Thirty-six patients were evaluable for PSA response to the first course of enzalutamide (±PROSTVAC). The median PSA decline was >99% (range 84->99%) (figure 2A). Although median time to first PSA rise after completing 84 days of enzalutamide was 28 days, the range was broad (14–182 days) and the median time until PSA recovery to respective baseline value was 224 days (84–1246) after the short-course of therapy (figure 2B).
Figure 2 (A) This waterfall plot depicts maximum PSA response for each individual patient who completed the full 84-day initial course of enzalutamide. For the 28 patients who were treated with a second course of enzalutamide when PSA recovered to baseline after course 1 (including 2 patients who discontinued for toxicity) a paired bar is included. (B) The swimmers plot depicts the duration of PSA control below baseline for each individual patient including the 84-day course of enzalutamide (median = 224 days after treatment, 308 days including treatment). For the 26 patients who completed a second course of enzalutamide, a paired bar is included (median = 189 days after treatment, 273 days including treatment).
An amendment allowed for retreatment with 84 days of enzalutamide (without vaccine) and for those 26 patients the median PSA decline was again >99% (87->99) with a median time to recovery to second baseline PSA of 189 days (78–400) (figure 2). (Three patients on second course of therapy discontinued for toxicity (see below) and one discontinued due to travel logistics.) Only two patients on study developed metastatic disease; one was 451 days after starting treatment on cycle 1 and another was treated with two courses and had metastasis 574 days after initiating therapy.
Toxicity
The treatment of enzalutamide in the absence of ADT was well tolerated with a grade 3 event (elevated alanine aminotransferase/aspartate aminotransferase) seen in two patients one of whom was taking a prohibited herbal supplement (table 2). Resolution of most toxicities was rapid within weeks of discontinuing enzalutamide in cycle 1. Vaccine-related toxicity (injection site reactions and flu-like symptoms) was seen frequently in the PROSTVAC cohort as expected. Fatigue was the most frequent adverse event seen (89% of all patients), but mostly grade 1 and transient with only seven patients (18%) having grade 2 fatigue at any time point, regardless of vaccine. Breast tenderness was seen in most patients (82%) but was universally grade 1 and likely in relation to elevation in systemic levels of testosterone. The second course of enzalutamide was stopped for precautionary reasons for dizziness and mild cognitive issues, in two patients respectively.
Table 2 Adverse events
Adverse Event Enzalutamide+Prostvac (n=20) Enzalutamide alone (n=18) Total for all patients (n=38)
Grade 1 Grade 2 Grade 3 Grade 1 Grade 2 Grade 3 Grade1 Grade 2 Grade 3
Injection Site Reaction 14 (70%) 4 (20%) 0 0 0 0 14 (37%) 4 (11%) 0
Flu-like Symptoms 6 (30%) 0 0 0 0 0 6 (16%) 0 0
Fatigue/Lethargy 14 (70%) 4 (20%) 0 13 (72%) 3 (17%) 0 27 (71%) 7 (18%) 0
Breast Pain/Nipple Tenderness 17 (85%) 0 0 14 (78%) 0 0 31 (81%) 0 0
Gynecomastia 6 (30%) 1 (5%) 0 8 1 (6%) 0 14 (37%) 2 (5%) 0
Myalgia 4 (20%) 0 0 1 (6%) 0 0 5 (13%) 0 0
AST/ALT Elevation 0 0 1 (5%) 3 (17%) 0 1 (6%) 3 (8%) 0 2 (5%)
Anorexia 5 (20%) 0 0 2 (11%) 0 7 (39%) 0 0
Dizziness 3 (15%) 1 (5%) 0 2 (11%) 2 (11%) 0 5 (28%) 3 (8%) 0
Headache 5 (25%) 1 (5%) 0 1 (6%) 0 0 6 (33%) 1 (3%) 0
Hypertension 0 1 (5%) 0 1 (6%) 1 (6%) 0 1 (6%) 2 (5%) 0
Hot Flashes 4 (20%) 1 (5%) 0 2 (11%) 0 0 6 (16%) 1 (3%) 0
Memory Impairment 3 (15%) 0 0 1 (6%) 0 0 4 (11%) 0 0
Anemia 6 (30%) 0 0 4 (22%) 0 0 10 (26%) 0 0
Decreased White Blood Cells 5 (25%) 2 (10%) 0 3 (17%) 0 0 8 (31%) 2 (5%) 0
Decreased Libido 3 (15%) 0 0 1 (6%) 0 0 4 (22%) 0 0
Testosterone
Testosterone increased in 22 of 36 patients beyond the institutional normal range, with a median rise to 834 ng/dL (range 308–1579) with course 1 of enzalutamide and 721 ng/dL (227–1171) in course 2. Testosterone declined from peak values in patients on enzalutamide within 4–6 weeks of completing the 84-day course of therapy.
Antigen-specific T cell responses, peripheral immune subsets, and thymic activity
Antigen-specific T cells targeting PSA were expanded after 3 months of therapy in a similar frequency of patients treated with enzalutamide alone (7/15, 45%) versus enzalutamide + vaccine (6/15, 40%). Similar findings were observed after 7 months of treatment, with 6/15 (40%) patients receiving enzalutamide alone and 8/15 (53%) patients receiving enzalutamide + vaccine displaying increases in PSA-specific T cells.
Analyses of PBMC subsets in patients treated with enzalutamide alone and in combination with vaccine revealed mainly immune potentiating effects (online supplemental table 1). Patients treated with enzalutamide alone had increases in NK cells (figure 3A), including mature NK cells and Tim3+ NK cells, as well as reductions in the immune suppressive MDSC compartment, including granulocytic MDSC (gMDSC, figure 3C) and programmed death ligand 1 (PD-L1+) MDSCs. Similar increases in the NK compartment were observed in patients treated with enzalutamide plus vaccine (figure 3B); however, here there were no reductions in the MDSC compartment (figure 3D), and instead were increased in activated CD4 that coexpress inducible T cell costimulator (ICOS) and programmed cell death protein 1 (PD-1) (figure 3F). Although activated CD4 were increased only in the combination arm (Figure 3E, F), it is unclear whether these cells are antigen and/or vaccine specific. Representative flow plots of notable subsets that change with therapy are shown in online supplemental figure 3.
10.1136/jitc-2020-001556.supp1 Supplementary data
10.1136/jitc-2020-001556.supp4 Supplementary data
Figure 3 Frequency of notable PBMC subsets changing during enzalutamide +/-vaccine therapy. Increase in natural killer cells in patients treated with enzalutamide alone (A) or enzalutamide + vaccine (B). Decrease in granulocytic myeloid derived suppressor cells (gMDSC) in patients treated with enzalutamide alone (C), but not in patients treated with enzalutamide + vaccine (D). Increase in ICOS+PD1+ CD4 T cells in patients treated with enzalutamide + vaccine (F), but not in patients treated with enzalutamide alone (E). Subsets with a potentially biologically relevant change are were defined as those with p <0.05, the majority of patients having a >25% change, difference in medians >0.05% of PBMCs, and a frequency >0.1% of total PBMCs. (Wilcoxon signed ranked test was used in this analysis).
TRECs were increased in the majority of evaluated patients (9 of 12) while on treatment with enzalutamide at time points between 15 and 86 days after initiation; TRECs were similarly increased in patients treated with enzalutamide combined with vaccine (figure 4). Furthermore, age was not a determining factor in the magnitude of increase in TRECs (r=0.21; p=0.49). There was a declining trend of decreasing mean TREC levels noted within 14 days of stopping enzalutamide (p=0.064).
Figure 4 Percent change in TREC after Therapy. Data in graphs indicates the % change in TREC/TRAC levels at the indicated time points after vs before therapy. Frequency and percentage of patients with increase in TREC are indicated. Bars indicate mean +/- SEM. DNA (100 ng) isolated from PBMCs was amplified to detect TREC and the housekeeper gene TRAC (T cell receptor alpha constant gene) using primer and probe sequences that have been previously described.19 Mean Ct values for the target gene (TREC) were normalized to mean Ct values for the housekeeping gene (TRAC) [–ΔCt = Ct(TRAC) – Ct(TREC)]. The ratio of expression of the target gene TRAC versus TREC was defined as 2(–ΔCt).20
Serum VEGF
There was no significant difference in the VEGF concentrations between those patients whoreceived PROSTVAC and those who received enzalutamide monotherapy. Eleven patients were evaluated during both courses of enzalutamide, while five were evaluated only in course 1 and six were evaluated only in course 2. The mean pretreatment plasma VEGF concentration was 192 pg/mL, SD of 82 pg/mL, median 174 pg/mL. VEGF concentrations were compared over the course of treatment using paired, Wilcoxon signed rank test, and no significant difference was seen in plasma VEGF concentration over the course of treatment (online supplemental figure 4).
10.1136/jitc-2020-001556.supp5 Supplementary data
Discussion
Since this trial was initiated, it is important to note that PROSTVAC alone failed to improve survival in a phase 3 trial in mCRPC.15 Although the use of PROSTVAC with enzalutamide did not improve PSA recovery rates, there was a more recent study of PROSTVAC alone in a similar nmCSPC population that suggested that PROSTVAC alone could induce delayed PSA declines in a subset of patients.31 Given the efficacy of enzalutamide to induce a median PSA decline of 99%, it seems likely that any PSA signal of PROSTVAC efficacy was lost in that substantial response to enzalutamide, although it is noteworthy that the three patients with the greatest duration of PSA response below baseline in this study (for 861, 1008, and 1442 days, respectively) received vaccine with enzalutamide. Interestingly, there were increases in CD4 markers of activity (ICOS and PD-1) that were seen in the vaccine arm, but not the enzalutamide alone arm.
Despite the lack of an efficacy signal of enzalutamide and vaccine, this study is notable because it demonstrates for the first time that short-course enzalutamide (regardless of vaccine and without ADT) in nmCSPC brought about prolonged PSA control well beyond the treatment period and such responses were largely duplicated with a second course of enzalutamide for 3 months. The median duration of 224 days after 84 days of treatment until PSA recovery to baseline means that for men with nmCSPC and rising PSA, a 3 month course of enzalutamide afforded them PSA control (ie, PSA below baseline) for 308 days (11 months) and a second 3 month course in eligible patients afforded them another median 273 days (9.75 months) with a PSA below baseline. It is perhaps not surprising that some benefit was diminished in duration of the second course (although median PSA declines were >99% in both groups). For the two patients who had metastatic recurrence at first and second PSA rise, it was only after an extended response of 451 and 574 days, respectively. These findings are noteworthy because it suggests that men with nmCSPC who may have been treated previously with continuous or intermittent ADT may now experience effective PSA control with intermittent short-course enzalutamide and less toxicity than ADT.
In addition to intermittent ADT, there have been other short-course therapy strategies explored in men with nmCSPC but they appear to be either more toxic and/or less effective. One study administered 80 mg of bicalutamide monotherapy for 2 years in men postprostatectomy (with no minimum required PSA DT).32 Of 91 patients on the continuous regimen, 26.4% had progression within 2 years, but 33% remain without progression at 5 years. Perhaps this study in an unselected population further highlights the potential role of androgen receptor disruption as monotherapy for abbreviated courses. Higher doses of bicalutamide have been investigated in this population, but also had increased toxicity.33 A more recent strategy evaluated an 8 month course of abiraterone with ADT versus ADT alone in 197 men with nmCSPC. The results suggest that the addition of abiraterone to ADT improved PSA-free survival from a median of 21.1 months to 28.3 months, but the use of ADT increased the toxicity profile of this strategy.34
While some practitioners hold firm to the stance of not treating nmCSPC until the development of metastatic disease, there may be some benefits to the use of ADT in clinical practice. Some patients have anxiety about rising PSA levels and ADT, despite its side effects, may improve quality of life by decreasing anxiety along with PSA. (Our future studies in nmCSPC will look into quality of life impact prospectively). Another major concern is that not all men with nmCSPC develop metastasis. While that is an accurate statement, subsets of patients with rapid PSA DTs less than 3 months have a 50% chance of developing metastasis within 1 year.9 Such populations should be considered for more aggressive therapies to prevent metastasis and the morbidity associated with metastatic disease. Patients who develop metastasis will require ADT indefinitely and then must contend with the associated toxicities. If the use of intermittent short-course enzalutamide can control PSA for nearly a year, and then be repeated with minimal diminishing benefit and toxicity, it is possible that such PSA control would come with a delay in metastasis in men who have rapidly rising PSAs. Thus, short-course enzalutamide could potential defer the need for indefinite ADT (and associated toxicities) in these patients, although future trials would be required to confirm this hypothesis.
The previous study of enzalutamide in nmCSPC was associated with some degree of toxicity, which was similarly seen in this trial (with grade 1 fatigue and breast/nipple pain predominating, and rare grade 3 toxicities). While these symptoms may appear minor, it is important to recall that nmCSPC patients have no cancer-related symptoms and thus these likely cumulative symptoms will impact quality of life over time and could diminish treatment compliance. Such toxicities are likely to be apparent in the ongoing EMBARK trial (NCT02319837), a phase 3 trial evaluating enzalutamide ± ADT in nmCSPC. Much like intermittent ADT was associated with improved quality of life due to periods where patients were not on therapy, it is likely that intermittent enzalutamide could afford similar benefits, as this study demonstrates, while also being associated with prolonged PSA control.12
The immunologic impact of enzalutamide independent of vaccine in this study is important as well. To our knowledge, the immune effects of enzalutamide without ADT have not been previously reported. Enzalutamide was associated with increased subpopulations of activated NK cells and decreases in immune suppressive gMDSCs. Emerging data have suggested that within the prostate cancer immune microenvironment NK cells and MDSCs may be more relevant than T cells.35 36 The apparent minimal impact seen on T cells after enzalutamide alone could provide insight into the recent phase 3 trial that demonstrated no improvement when the PDL1 targeting antibody atezolizumab was added to enzalutamide in advanced prostate cancer.37
We also report for the first time in humans that an androgen receptor targeting therapy can increase naïve T cell production from the thymus in humans. TRECS are the byproduct of T cell receptor gene rearrangement that occurs when naïve T cells are produced from the thymus, thereby providing an indirect measure of thymic activity. Previous studies have shown that androgen blockade in mice and humans activates thymic regeneration and increases TREC levels.38 Similar to androgen deprivation, 2 weeks of enzalutamide treatment in C57BL/6 mice increased thymic weight and TREC production.14 The increases in TRECs coincided with therapy, irrespective of age. Interestingly, even though the impact of enzalutamide on the PSA often lasts months after therapy, TREC levels appeared to decline 2 weeks after enzalutamide discontinuation.
There was no clear association between clinical responses and immune changes, but most patients in this study had sustained PSA declines of large magnitude so such associations may not be readily apparent in a trial of this size.
The immune findings in this study are remarkable because, beyond sipuleucel-T, immune checkpoint inhibitors are only effective in about half of patients who possess rare mutations like microsatellite instability and CDK12 inactivation.39 40 Since enzalutamide is already frequently used in many stages of prostate cancer, additional immunotherapies can be added to exploit the immune potentiating effects of enzalutamide on NK cells and gMDSCs. While PD1/PDL1 inhibitors are often dependent on T cells infiltrating the tumor for their effects, other immunotherapies such as immunocytokines could be combined with enzalutamide to bring about a synergistic clinical impact. The findings of this study highlight that the best opportunities may lie in focusing on NK cells when developing immune-based combinations with enzalutamide. Additional strategies could be built on enzalutamide’s ability to enhance TRECs and possibly be used beyond prostate cancer.
Although the trial is small in numbers, the median PSA decline of >99% is likely to be a reasonable indicator of the potential for short-course enzalutamide in nmCSPC. While the responses to the second course of enzalutamide are encouraging, it should be noted that some degree of selection bias may have impacted why some patients did not receive a second course, either by protocol requirement or other factors.
A shortcoming of this trial stems from the fact that it was initiated in 2013; thus it did not incorporate modern positron emission tomography (PET) or molecular imaging strategies, which are increasingly being used in clinical practice. It is worth noting that many patients with nmCSPC are likely to have micrometastatic disease detectable on sensitive PET imaging studies.41 Nonetheless, these findings on ultra-sensitive modern imaging studies do not meet the conventional definition of metastasis as they have been defined in mCSPC clinical trials to this point (that is findings on CT/MRI or Tc99 bone scan). While some practitioners may contend that PET scan findings define metastatic disease that should be treated with docetaxel or antiandrogen therapies based on studies of those agents in overtly metastatic disease (as seen on CT and Tc99 bone scan), prospective data supporting this are lacking in either mCSPC or mCRPC trials where modern imaging techniques were not employed. Others may suggest radiation has an emerging role in oligometastatic prostate cancer;however, its role in oligorecurrence (rising PSA with negative conventional imaging after definitive therapy) is less defined.
Future studies of agents such as enzalutamide in nmCSPC need to be done to better understand their clinical role in this minimal residual disease state of prostate cancer. The data presented here provide a rationale for intermittent use of enzalutamide in men with biochemically recurrent prostate cancer that can impact PSA and thus likely decrease near term risk of metastatic disease, without the systemic toxicity of ADT. In order to define the impact beyond just PSA, such studies should require baseline and follow-up assessments with modern (PET) imaging to better understand the antitumor effects that are associated with transient but substantial and repeatable PSA declines such as those seen with short-course enzalutamide in this study. If such responses are associated with changes in PET imaging (ie, improvements) and/or the delay in ultimate progression of disease in PET or conventional imaging, then perhaps such an intermediate endpoint could be evaluated in phase 3 trials, as has been suggested by data from the ICECaP Working Group, demonstrating a strong association between metastasis-free survival and overall survival in localized disease.42 Indeed, modern imaging has potentially lifted the shroud of nmCSPC, allowing for more pragmatic treatment of the minimal residual disease state in patients who are at high risk for metastasis.
Editorial acknowledgement. Debra Weingarten, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute.
Twitter: @Dr_RaviMadan, @mbilusic, @gulleyj1
Contributors: RAM—conceptualization, methodology, validation, investigation, formal analysis, writing—original draft, visualization, supervision, project administration, funding acquisition. FK—investigation, writing—review and editing. RD—methodology, investigation, formal analysis, writing—original draft. MA-H—formal analysis, writing—original draft. MB—investigation, writing—review and editing. ILR—investigation, writing—review and editing. HS—investigation, writing—review and editing. PMA—investigation, writing—review and editing. MRT—investigation, writing—review and editing. JLM—investigation, writing—review and editing, formal analysis. LMC—investigation, writing—review and editing. AC—investigation, writing—review and editing. AH—investigation, writing—review and editing. MW—investigation, writing—review and editing. NH—investigation, writing—review and editing, data curation. HO—investigation, writing—review and editing, data curation. SEL—investigation, writing—review and editing. CHC—investigation, writing—review and editing. SMS—investigation, writing—review and editing, conceptualization. WDF—investigation, writing—review and editing. JS—investigation, writing—review and editing. WLD— investigation, writing—review and editing, conceptualization, resources. JLG—investigation, writing—review and editing, conceptualization, resources.
Funding: This study was funded by the Intramural Program at the National Cancer Institute, Bethesda, Maryland, USA. It was also supported with drug supply from Astellas Pharma Global Development/Pfizer and Bavarian Nordic.
Competing interests: No, there are no competing interests.
Patient consent for publication: Not required.
Ethics approval: All patients signed Institutional Review Board-approved informed consents.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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. | Recovered | ReactionOutcome | CC BY-NC | 33664086 | 9,674,970 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis'. | Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis.
Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.
Introduction
Treatment with anti-programmed cell death protein-1 (αPD-1) alone or combined with anti-cytotoxic T-lymphocyte-associated protein 4 (αCTLA-4) has greatly improved the prognosis of metastatic melanoma with a substantial fraction of patients achieving long-lasting partial or complete clinical responses1–6. The principal limitation of αPD-1/αCTLA-4 dual therapy is the relatively high rate of immune-related complications, which commonly include colitis, hepatitis and thyroiditis, but may also include pneumonitis, myocarditis and encephalitis7,8. Such adverse events range from mild reactions to life-threatening presentations, but are nevertheless clinically significant incidents that influence patient management9,10. Avoidance of complications has led to a somewhat complicated treatment decision-making process (Fig. 1a) that seeks to balance individual risk and capacity to tolerate adverse reactions against the superior clinical responses achieved with dual αPD-1/αCTLA-4 therapy over αPD-1 monotherapy11–13.Fig. 1 Individual predisposition to hepatitis after αPD-1/αCTLA-4 treatment.
a Individualised treatment of melanoma is guided by tumour staging, presence of B-RAF mutations and fitness-for-toxicity. b Colitis, hepatitis and thyroiditis are common immune-related complications of dual therapy with Nivolumab plus Ipilimumab; 31.4% of patients experienced two or more of these immune-related adverse reactions (n = 89). c Colitis, hepatitis and thyroiditis occurred independently and were not significantly associated with clinical response (n = 89; F.E). d–h Patients who developed hepatitis of any grade following dual therapy lacked biochemical signs of liver inflammation before treatment. In particular, no clinically meaningful differences in plasma levels of d aspartate transaminase (AST; n = 87; M.W.; Bonferroni-corrected p-value, m = 5), e alanine transaminase (ALT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), f gamma glutamyl transaminase (γ-GT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), g total bilirubin (n = 87; M.W.; Bonferroni-corrected p-value, m = 5), or h C-reactive protein (CRP; n = 85; M.W.; Bonferroni-corrected p-value, m = 5) were observed between patients who developed hepatitis and those who did not. Median values are indicated by a red line. i, j Biochemical markers of tumour burden were not different between patients who developed hepatitis and those who did not. i Pre-treatment levels of lactate dehydrogenase (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. j Pre-treatment levels of protein S100 (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). k–m No association was observed between seropositivity for k hepatitis B virus core antigen (HBcAg; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), l hepatitis C virus (HCV; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), or m hepatitis E virus (HEV; n = 67; F.E.; Bonferroni-corrected p-value, m = 3) and development of hepatitis following dual therapy. n No association was observed between rounds of αPD-1/αCTLA-4 administered and development of hepatitis (n = 89; M.W.).
Our aetiological understanding of colitis, hepatitis and thyroiditis caused by immune checkpoint blockade remains incomplete14; however, these treatment-related conditions are clearly different from known autoimmune diseases15,16. Such adverse reactions are usually attributed to generalised dysregulation of T cells17,18 or autoantibodies15. Here, we explore a different view—namely, that individual patients are predisposed to particular treatment-related complications by virtue of pathogen-specific memory T cells present in their repertoire before immune checkpoint blockade is given.
Cytomegalovirus (CMV) seroprevalance amongst European adults is over 50%. Primary CMV infection usually presents during young adulthood as an acute febrile illness, after which life-long latency is established. The exact sites and mechanisms of CMV latency are not fully resolved, but myelomonocytic cells in blood and tissues are major reservoirs19. CMV reactivation characteristically follows immune compromise caused by immunosuppressive therapy or other viral infections20. Clinical manifestations of CMV reactivation are variable, ranging from classic febrile illness to tissue-invasive disease presenting as colitis, hepatitis, pneumonitis or encephalitis21. Reactivation of CMV causes cellular injury through the cytopathic effect of viral replication, but more conspicuously through triggering T cell immunity. Pneumonitis in transplant recipients illustrates how CMV-reactive T cells provoke extensive, life-threatening inflammation despite low-level viral replication22. Even in anatomical locations from which T cells are normally excluded, such as the retina, T cell-mediated responses significantly contribute to CMV-related disease. Thus, low-level and compartmentalised reactivation of CMV can be responsible for serious acute immunopathology in humans23–25.
Cycles of CMV latency and reactivation lead to a now well-recognised phenomenon of memory inflation, which is typified by failure of primed CMV-specific CD8+ T cell populations to contract and give rise to central memory T cells26. Instead, a dominant pool of effector memory CD8+ T cells that does not become functionally exhausted is maintained27. Such inflationary CD8+ T cells achieve high frequencies over time, sustained through repetitive stimulation by viral reactivation or long-term persistence of viral antigens28. Memory inflation is described as an exclusive feature of CD8+ effector T cell responses, although durable expansion of CMV-specific CD4+ T cells can occur in transplant recipients29.
This study identifies pre-therapy expansion of CD4+ effector memory T cells (TEM) in CMV-infected patients with metastatic melanoma as a prognostic marker of αPD-1/αCTLA-4-related hepatitis. Opting for αPD-1 monotherapy or prophylactic valganciclovir in CMV IgG+ patients with unresectable metastatic disease and pre-treatment expansion of CD4+ TEM cells reduces their risk of hepatitis. We conclude that sub-clinical reactivation of CMV plays a previously unsuspected role in the immunopathogenesis of αPD-1/αCTLA-4-related hepatitis in a subgroup of patients.
Results
Clinical features do not predict αPD-1/αCTLA-4-related hepatitis
If immune-related complications of αPD-1/αCTLA-4 therapy resulted solely from treatment-induced immunological effects30,31, we might expect hepatitis, colitis and thyroiditis to coincide often32 (Fig. 1b). However, no such associations were found in a cohort of 89 patients with metastatic melanoma treated with αPD-1/αCTLA-4 dual therapy (Fig. 1c, Supplementary Fig. 1 and Supplementary Tables 1–3). This raises the possibility that some individuals are predisposed to particular adverse reactions.
In this study, we focused on factors that predispose to αPD-1/αCTLA-4-related hepatitis. Except for patients who developed hepatitis being generally younger (Supplementary Table 4) no associations were found between incidence of hepatitis and pre-treatment clinical variables (Supplementary Tables 4 and 5). Conventional biochemical markers of liver dysfunction, systemic inflammation or tumour burden did not discriminate between patients who did or did not develop hepatitis (Fig. 1d–j). We found no associations between incidence of hepatitis and seropositivity for hepatitis B virus (HBV), hepatitis C virus (HCV) or hepatitis E virus (HEV; Fig. 1k–m). Incidence of hepatitis was not greater with more rounds of αPD-1/αCTLA-4 therapy; in fact, as immune-related complications are reason to withhold treatment, patients who developed hepatitis tended to receive fewer rounds of αPD-1/αCTLA-4 (Fig. 1n). Autoimmune hepatitis-related autoantibodies were not associated with risk of hepatitis (Supplementary Table 6). In short, case history and routine clinical investigations did not predict hepatitis after dual therapy in our study cohort.
CD4+ TEM cell expansion predicts αPD-1/αCTLA-4-related hepatitis
We next profiled circulating leucocyte subsets immediately prior to start of dual therapy in a training set of n = 44 patients with unresectable metastatic melanoma (Supplementary Figs. 2–8). Comparing the frequency of 50 principal leucocyte subsets between patients who subsequently did (n = 18) or did not (n = 26) develop hepatitis revealed significant over-representation of CD4+ TEM cells associated with hepatitis (Fig. 2a, b). This observation was confirmed in a validation set (n = 45) of similar patients (Fig. 2c). Baseline expansion of CD4+ TEM cells was a fair discriminator (AUROC = 0.706) of patients who did or did not later develop hepatitis in the validation set (Fig. 2d). Strikingly, CD4+ TEM cell frequencies in all patients with completely resected disease were normally distributed with no extreme cases of baseline CD4+ TEM cell expansion, allowing us to set a threshold below which 99% of patients should fall (Fig. 2e). Applying this stringent cut-off to our validation cohort of patients with unresectable metastatic disease (Fig. 2f) allowed us to correctly predict hepatitis in 6 of 6 patients with CD4+ TEM≥21% (specificity = 100%) and correctly identify 6 of 20 patients who developed hepatitis (sensitivity = 30.0%). CD4+ TEM≥21% patients were not predisposed to colitis (Fig. 2g), thyroiditis or superior clinical responses to therapy (Supplementary Table 7). Hepatitis was not more severe in CD4+ TEM≥21% patients compared to CD4+ TEM<21% patients (Fig. 2h) and no difference in time-to-first presentation was observed (Fig. 2i). Hence, baseline CD4+ TEM expansion is a specific, but relatively insensitive prognostic marker of individuals who are predisposed to hepatitis after αPD-1/αCTLA-4 therapy. Owing to its low sensitivity, classifying patients as CD4+ TEM<21% has limited clinical utility; however, specifically identifying cases at high-risk of hepatitis before treatment is useful from a research perspective because we can then prospectively study the immunological basis of their predisposition.Fig. 2 Circulating CD4+ T effector memory cell frequency predicts hepatitis after Nivolumab plus Ipilimumab treatment.
a Peripheral blood samples were collected from melanoma patients with metastatic disease receiving αPD-1/αCTLA-4 therapy immediately before administration of the first dose (n = 89). Leucocyte subsets differentially represented in patients with or without hepatitis were identified in a randomly assigned training set (B.H.-corrected t-tests; n = 44; m = 50; FDR = 0.25). Red dots indicate significantly differently represented subsets. Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. b CD4+ TEM % in training set patients with or without treatment-related hepatitis (n = 44; M.W.). Median values are indicated by a red line. c CD4+ TEM % in validation set patients with or without treatment-related hepatitis (n = 45; M.W.). d ROC analysis of CD4+ TEM % as a discriminatory marker for treatment-related hepatitis in the validation set (n = 45). e Comparison of the bimodal distribution of CD4+ TEM % in patients with unresectable metastatic disease (n = 107) and the normal distribution (n = 49; K2 = 2.79; p = 0.248) of CD4+ TEM % in patients with completely resected tumours. A cut-off of CD4+ TEM ≥ 21% was set (indicated by a dashed red line) below which 99% of completely resected tumour cases should fall. Four pink points represent CD4+ TEM≥21% patients with metastatic disease who were electively treated with αPD-1 monotherapy. f In the validation set, 68.9% patients were correctly classified using a cut-off of CD4+ TEM ≥ 21 %, whereas 55.6% were correctly classified under the no-information model (n = 45; F.E.). g CD4+ TEM ≥ 21 % is not a marker of predisposition to αPD-1/αCTLA-4-related colitis (n = 89; F.E.). h CD4+ TEM≥21% patients did not experience more severe hepatitis than CD4+ TEM<21% patients (n = 38; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. i Time-to-first presentation of hepatitis was not different between CD4+ TEM≥21% (n = 12) and TEM<21% (n = 26) patients (log-rank). j Twelve of 12 patients with unresectable metastatic melanoma and CD4+ TEM ≥ 21% developed hepatitis after αPD-1/αCTLA-4 dual therapy. By contrast, 3 of 4 CD4+ TEM≥21% patients treated with αPD-1 monotherapy did not develop hepatitis (F.E.; p = 0.007).
Opting for αPD-1 monotherapy reduces risk of hepatitis
Although αPD-1 monotherapy achieves fewer sustained clinical responses in patients with metastatic melanoma, it causes fewer adverse reactions than αPD-1/αCTLA-4 dual therapy1. Therefore, there is a clear rationale for avoiding αPD-1/αCTLA-4 dual therapy in patients at risk of hepatitis. Four CD4+ TEM≥21% patients with metastasic disease presented during our study, but were electively treated with αPD-1 monotherapy (Fig. 2j). Whereas 12 of 12 CD4+ TEM≥21% patients treated with αPD-1/αCTLA-4 dual therapy developed hepatitis, 3 of 4 CD4+ TEM≥21% patients who received αPD-1 monotherapy remained hepatitis free. Reducing the incidence hepatitis by opting for αPD-1 monotherapy hints that CTLA-4 blockade may be mechanistically important for development of hepatitis in CD4+ TEM≥21% patients33.
CD4+ TEM frequency is an independent predictor of hepatitis
We next investigated possible causes of baseline CD4+ TEM expansion. To establish CD4+ TEM expansion as an independent risk factor, we first sought to exclude possible confounding covariables. Baseline CD4+ TEM≥21% was not related to sex, age or body-mass index (Supplementary Table 7 and Fig. 3a, b). No significant correlation was observed between baseline CD4+ TEM % and serum levels of C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT) or total bilirubin (Fig. 3c–g). Because glucose metabolism provides a reliable measure of liver inflammation34, we were able to further rule out liver inflammation prior to therapy as a predisposing cause of CD4+ TEM≥21% hepatitis by estimating hepatic glucose uptake in patients who underwent 18F-fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT studies as part of routine tumour staging shortly before starting immunotherapy (Fig. 3h). This retrospective comparison showed 18F-FDG standard uptake ratios (SURmean liver) were higher in CD4+ TEM<21% patients than CD4+ TEM≥21% patients with hepatitis (Fig. 3i). Therefore, our biochemical and radiological investigations argue against pre-treatment liver inflammation as a common cause for baseline CD4+ TEM expansion and treatment-related hepatitis.Fig. 3 CD4+ TEM frequency is an independent predictor of αPD-1/αCTLA-4-related hepatitis.
a CD4+ TEM % did not correlate with age (n = 89; Pearson). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM % did not correlate with body mass index (n = 89; Pearson). c CD4+ TEM % did not correlate with C-reactive protein (CRP) levels (n = 85; Pearson). d CD4+ TEM % did not correlate with aspartate aminotransferase (AST) levels (n = 87; Pearson). e CD4+ TEM % did not correlate with alanine aminotransferase (AST) levels (n = 89; Pearson). f CD4+ TEM % did not correlate with gamma-glutamyltransferase (γ-GT) levels (n = 89; Pearson). g CD4+ TEM % did not correlate with total bilirubin levels (n = 89; Pearson). h Glucose metabolism measured by 18F-fluoro-2-deoxy-d-glucose (18F-FDG) uptake in PET/CT studies is a quantitative marker of liver inflammation. Calculating standard uptake ratio (SURmean Liver) allows accurate quantification of 18F-FDG uptake in liver by correcting for differential clearance of tracer from blood and liver parenchyma. Higher SURmean Liver values indicate more severe inflammation. T0 = reference time point at 75 min post-injection and T = actual scan time. i SURmean Liver was lower in CD4+ TEM≥21% patients than CD4+ TEM<21% patients who developed hepatitis indicating less inflammation at baseline in the CD4+ TEM≥21% subgroup (n = 28; Pearson). j CD4+ TEM≥21% was not associated with the number of organs containing one or more metastases ≥1.5 cm in diameter (n = 103; F.E.). k CD4+ TEM≥21% was not associated with the presence of hepatic metastases (n = 103; F.E.). l CD4+ TEM % did not correlate with lactate dehydrogenase (LDH) levels (n = 88; Pearson). m CD4+ TEM % did not correlate with protein S100 levels (n = 88; Pearson). n CD4+ TEM≥21% was not associated with any prior therapy (n = 89; F.E.).
Because CD4+ TEM expansion is principally a feature of metastatic melanoma (Fig. 2e), we next asked whether CD4+ TEM% was somehow associated with tumour burden. No relationship was found between CD4+ TEM% and the number of organs containing metastases, presence of hepatic metastases or serum lactate dehydrogenase (LDH) and protein-S100 serum levels (Fig. 3j–m and Supplementary Table 7). There was a tendency for CD4+ TEM≥21% patients to have received previous therapy of any type (including BRAFi/MEKi or Talimogen laherparepvec) but besides implying a longer disease course before starting dual therapy, we see no mechanistic interpretation because these drugs share no common pharmacological action (Fig. 3n). In short, we found no obvious clinical association to explain the predisposition of CD4+ TEM≥21% patients to hepatitis.
CD4+ TEM cell expansion is associated with chronic T cell activation
Although CD4+ T cell counts were not different between CD4+ TEM<21% and CD4+ TEM≥21% patients (Supplementary Table 7), there were significantly fewer circulating naïve T cells in CD4+ TEM≥21% patients (Fig. 4a). This reduction was complemented by increased absolute numbers of CD4+ TEM and TEMRA cells (Fig. 4b, c) whereas central memory T cell (TCM) counts tended to be lower in CD4+ TEM≥21% patients (Fig. 4d). We next defined other leucocyte subsets that correlated with CD4+ TEM % in both our training and validation cohorts (Fig. 4e). Most covariant populations were T cells, particularly CD4+ T cell subsets. Changes in the CD4+ T cell compartment of TEM≥21% patients were consistent with chronic activation, particularly downregulation of CD27 and upregulation of CD57, HLA-DR and CD279 expression (Fig. 4f–i). Similar differences were detected in CD8+ T cells (Supplementary Fig. 9). Notably, CD4+ TEM≥21% patients tended to have higher frequencies of CD160+ CD244+ exhausted CD8+ T cells than CD4+ TEM<21% patients (Fig. 4j).Fig. 4 CD4+ TEM cell enrichment is associated with chronic activation and increased numbers of effector memory CD4+ T cells.
a–d Increased CD4+ TEM frequency before treatment reflects a decrease in circulating naïve CD4+ T cells and an increase in circulating numbers of CD4+ TEM cells. a Baseline naïve CD4+ T cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 5.2 ⨯ 10−5). b Baseline CD4+ TEM cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 8.0 ⨯ 10−4). c Baseline CD4+ TEMRA cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). d Baseline CD4+ TCM cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. e Pairwise correlations between CD4+ TEM cell frequency and other leucocyte subset frequencies in the training and validation sets (n = 103; Pearson). Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. f Baseline CD27+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.2 ⨯ 10−10). g Baseline CD57+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 2.0 ⨯ 10−9). h Baseline HLA-DR+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.1 ⨯ 10−5). i Baseline CD279+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). j Baseline CD160+ CD244+ CD8+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). k Baseline Torque Teno Virus (TTV) loads. Uninfected patients were censored from analysis (n = 74; M.W.; Bonferroni-corrected p-value, m = 60). Median values are indicated by a red line.
Most adults are persistently infected with Torque Teno Virus (TTV), a non-enveloped, circular, single-stranded DNA virus of the Anellovirus family that causes no apparent disease. T cell immunity controls TTV replication in healthy people, whereas TTV copy number in immunocompromised individuals is increased; therefore, TTV load in plasma is a useful marker of immune competence. Despite accumulating chronically activated and exhausted T cells, TTV load in CD4+ TEM≥21% versus CD4+ TEM<21% patients was not different, implying that CD4+ TEM≥21% patients are not generally immunocompromised (Fig. 4k).
CD4+ TEM cell expansion correlates with immunity to CMV
To briefly summarise, baseline expansion of CD4+ TEM cells identifies a subset of patients with metastasic melanoma who are predisposed to αPD-1/αCTLA-4-related hepatitis. These patients show signs of persistent or recurrent CD4+ and CD8+ T cell responses35, but are otherwise clinically and immunologically unremarkable. It is usually very difficult to isolate factors responsible for such a non-specific immunological picture36. Fortunately, a surprising pattern emerged from our dataset: CD4+ TEM≥21% patients mostly presented between September and February (Fig. 5a). This seasonal influence was apparent over all 4 years of the study, leading us to think that CD4+ TEM expansion might be driven by a pathogen. Active infections with hepatitis viruses, including HBV and HCV, are relative contraindications to αPD-1/αCTLA-4 therapy (Supplementary Table 7), so we were forced to consider possible involvement of other hepatotropic viruses, such as HEV and herpesgroup viruses.Fig. 5 CD4+ TEM cell expansion correlates with immunity to cytomegalovirus.
a Seasonal presentation of CD4+ TEM≥21% patients between 2017 and 2020 (n = 103; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM≥21% status was associated with high serum levels of anti-CMV IgG antibodies (n = 100; F.E.; p = 1.2 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. c CD4+ TEM≥21% status was associated with CMV-reactivity in pp65 ELISPOT (n = 53; F.E.; p = 9.0 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. d Development of hepatitis was associated with CMV-seropositivity and CD4+ TEM≥21% status (n = 89). Median values are indicated by a red line. e ROC analysis showing CD4+ TEM % is a superior discriminator of patients at risk of hepatitis when considering only CMV IgG+ cases as opposed to all cases. f Classification of patients with unresectable metastatic melanoma who did or did not develop αPD-1/αCTLA-4-related hepatitis according to CMV IgG status and baseline CD4+ TEM cell frequency using a revised cut-off of CD4+ TEM ≥ 16%. Red boxes indicate 34 of 40 (85%) cases correctly classified by our model (n = 40; F.E.; p = 1.4 ⨯ 10−5). Green box indicates 2 of 17 (11.7%) cases predicted to develop hepatitis who did not. Pink box indicates 4 of 23 (17.4%) cases predicted not to develop hepatitis who did. Blue box indicates 19 of 49 CMV IgG− patients not considered by our model who developed hepatitis.
Latent CMV infection is prevalent amongst European adults and involves many organs, including liver. Compartmentalised reactivation of CMV infection occurs in immunocompromised individuals and those with concomitant viral upper respiratory tract infections20. In our patients, we found a strong association between serum CMV-specific IgG antibody levels and CD4+ TEM status (Fig. 5b). Furthermore, T cell reactivity against CMV pp65 peptides in an IFN-γ enzyme-linked immunospot (ELISPOT) assay was tightly associated with CD4+ TEM status (Fig. 5c). These results led us to hypothesise a causal relationship between compartmentalised, sub-clinical CMV reactivation in liver and chronic enrichment of CD4+ TEM cells in blood.
Because baseline CD4+ TEM cell expansion was mainly a feature of CMV IgG+ patients (Fig. 5d), we next asked whether incorporating CMV IgG status could improve our predictive model. When considering only CMV IgG+ cases, CD4+ TEM % was a more discriminatory marker of hepatitis (Fig. 5e). Therefore, using our training set filtered for CMV IgG+ cases, we revised our cut-off to CD4+ TEM ≥ 16% in CMV IgG+ cases in order to achieve a better compromise between specificity and sensitivity (Supplementary Fig. 10). The new cut-off performed well in the validation set with a correct classification rate of 81.0% (positive predictive value (PPV) = 85.7% and negative predictive value (NPV) = 78.6%) compared to 42.9% under the no-information model.
For descriptive purposes, we can consider the distribution of patients from the combined training and validation sets according to CMV IgG and CD4+ TEM status (Fig. 5f). Our predictive model explains the occurrence of hepatitis in 34 of 89 (38.2%) of all patients (red boxes). Two of 17 (12%) CMV IgG+ CD4+ TEM≥16% patients (green box) did not develop hepatitis: one of these received four rounds of αPD-1/αCTLA-4 therapy and registered no complications; however, the other received only 1 round of αPD-1/αCTLA-4 before treatment with prednisolone from weeks 2 to 7 for colitis. We speculate 4 of 23 CMV IgG+ CD4+ TEM<16% patients who were incorrectly predicted as hepatitis-negative (pink box) were sampled at an early stage of CD4+ TEM cell expansion and our test was not sensitive enough to discriminate the change. Our model does not explain why 19 of 49 CMV IgG− patients developed hepatitis (blue box) but we believe these represent an aetiologically distinct subset.
CMV-reactive CD4+ T cells are enriched in CD4+ TEMhigh patients
We next asked whether CMV-reactive CD4+ T cells were enriched in patients with baseline CD4+ TEM expansion. Peripheral blood mononuclear cells (PBMC) were stimulated in culture for 18 h with CMV lysates before IFN-γ, TNFα, IL-17, IL-4 and CD69 expression was measured by flow cytometry (Fig. 6a and Supplementary Figs. 11 and 12). To detect hyporesponsive CMV-specific T cells, paired cultures were also stimulated in the presence of neutralising antibodies against PD-1 and CTLA-4. In contrast to CMV IgG− and CMV IgG+ CD4+ TEM<16% patients, we readily detected IFN-γ-producing, CMV-reactive CD4+ T cells in CMV IgG+ CD4+ TEM≥16% patients (Fig. 6b). This difference implies a higher number of circulating IFN-γ-producing, CMV-reactive CD4+ T cells (Fig. 6c). Proportions of CMV-reactive CD4+ T cells expressing IL-17, IL-4 or only TNFα were too low to quantify accurately.Fig. 6 CMV-reactive CD4+ T cells are enriched in patients with CD4+ TEM cell expansion.
CMV-reactive CD4+ T cells in patients with unresectable metastatic melanoma were assayed by in vitro stimulation with CMV lysates (blue boxes). Neutralising antibodies (red hatching) were used to detect T cells unable to respond to CMV antigens owing to expression of PD-1 or CTLA-4. T cell responses were quantified by flow cytometry analysis of cytokine expression. a Example data from a CMV IgG+ CD4+ TEM≥16% patient who developed hepatitis. Gating of live, singlet, IFN-γ-producing CD4+ T cells is illustrated in Supplementary Fig. 11. b Frequencies of IFN-γ-producing CD4+ T cells in patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers. c Absolute numbers of circulating IFN-γ-producing CD4+ T cells patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers.
Valganciclovir reverses αPD-1/αCTLA-4-related hepatitis
Strong associations between T cell immunity against CMV, expansion of CD4+ TEM and risk of treatment-related hepatitis imply an underlying pathogenic mechanism; however, to demonstrate a causal relationship, we needed to establish that inhibiting CMV replication was effective in treating or preventing hepatitis. Valganciclovir is an anti-viral agent licensed for therapy and prophylaxis of CMV infections in immunocompromised patients. It is a widely used and safe drug with a well-known and broadly acceptable profile of adverse effects. Therefore, we next gave valganciclovir treatment to two patients with αPD-1/αCTLA-4-related hepatitis.
The first patient was a comparatively fit 54-year-old man with a new diagnosis of metastatic melanoma (Fig. 7a). Staging CT revealed multiple lung and bone metastases, but no metastasis to liver or lymph nodes. At baseline, the patient was CMV-IgG+ and CD4+ TEM = 18.7% (Fig. 7b). Nivolumab plus Ipilimumab were given at 0, 3 and 6 weeks. A fourth round of αPD-1/αCTLA-4 at week 9 was omitted owing to joint pain and the patient received two rounds of Denosumab (αRANKL). Nivolumab monotherapy was administered in weeks 12, 16, 20 and 24. Staging CT at week 14 showed a partial clinical response with significant regression of pulmonary metastases; hence, checkpoint blockade was of clear clinical benefit.Fig. 7 Case 1: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 54-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction, withdrawal and re-introduction of valganciclovir treatment. c The patient presented at the end of week 40 with recrudescent hepatitis and was treated with 900 mg/day valganciclovir for 2 days prior to liver biopsy. Histopathological image of the liver biopsy (H&E staining; scale bar 500 µm). d Generally, the liver parenchyma appeared normal (H&E staining; scale bar 100 µm). e Only a few lymphocytes and sparse necrotic hepatocytes were observed in portal areas with small bile plugs (arrows) with no signs of hepatitis (H&E staining; scale bar 100 µm).
The patient received a dose of αPD-1 monotherapy in week 32. Four weeks later, he presented in clinic with grade 4 hepatitis. Strong reactions against pp65 and IE-1 peptides were measured by ELISPOT. Accordingly, the patient was treated with 900 mg/day valganciclovir plus prednisolone. Liver function tests (LFTs) returned to normal, so over the subsequent 2 weeks, prednisolone was weaned and then valganciclovir was withdrawn. Seven days later, the patient returned to clinic with deranged LFTs. Valganciclovir and prednisolone were both reinstated, leading to a rapid normalisation of LFTs. Two days later, a for-cause liver biopsy was performed (Fig. 7c–e). The tissue was essentially normal, although a few dying hepatocytes and isolated lymphocytes were observed in the portal areas. Immunohistochemical staining for CMV and nested CMV PCR from fixed biopsy material were negative. The patient remained clinically stable for 9 days, so he was again weaned from prednisolone by the start of week 43; however, on this occasion, 900 mg/day valganciclovir treatment was continued. After complete withdrawal of prednisolone, while still receiving valganciclovir, the patient’s LFTs remained stable for a further 4 weeks. At the start of week 47, valganciclovir was withdrawn for a second time. Subsequently, the patient did not develop hepatitis and required no further steroids. The patient received further doses of αPD-1 monotherapy in weeks 54 and 58 without signs of recurrent liver injury. To us, this suggests the T cell antigens driving hepatitis in this patient were absent after valganciclovir treatment. In our clinical opinion, despite the absence of detectable virus, the patient’s fast recovery and unusual relapse of hepatitis are best explained by introduction, withdrawal and reintroduction of valganciclovir.
The second patient was a 49-year-old man who had an uncomplicated first year after αPD-1/αCTLA-4 and had been receiving Encorafenib/Binimetinib therapy for 7 weeks when he developed hepatitis in week 67 (Fig. 8a, b). Hepatitis failed to resolve despite withdrawal of B-RAFi/MEKi and escalating doses of prednisolone. 900 mg/day valganciclovir was introduced at the start of week 72 and a for-cause biopsy was performed on the same day (Fig. 8b). Four days later, the patient started a course of 1 mg/day mycophenolate mofetil. Strikingly, AST, ALT and γ-GT levels declined consistently from the day after valganciclovir was given, although total bilirubin continued to rise. Starting valganciclovir treatment appeared to be temporally related to increased reactivity in CMV IE-1 ELISPOT and a small decline in CD4+ TEM frequency.Fig. 8 Case 2: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 49-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction of valganciclovir treatment. c Histopathological image of a liver biopsy taken at the start of week 72 showing signs consistent with drug toxicity, autoimmunity or viral infection (H&E staining; scale bar 500 µm). d Extensive centrilobular necrosis (arrows) involving 30–40% of hepatocytes was observed (H&E staining; scale bar 100 µm). e Dense inflammatory infiltration of lymphocytes, eosinophils and neutrophils was seen in portal areas (H&E staining; scale bar 100 µm).
Liver biopsy revealed dense infiltration by lymphocytes, eosinophils and neutrophils with an accompanying ductal reaction (Fig. 8c–e). Extensive centrilobular hepatocyte necrosis was observed, which was also associated with inflammatory infiltration. These histopathological signs of significant liver damage could have been consistent with autoimmunity or viral infection. Both histological staining for CMV and CMV PCR from fixed biopsy material were negative. Although we were unable to detect virus, it is our clinical impression that markers of liver damage responded to valganciclovir treatment.
Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis
We next asked whether valganciclovir prophylaxis could prevent αPD-1/αCTLA-4-related hepatitis in predisposed individuals. The 50th, 75th and 90th percentiles of time-to-hepatitis in CMV-IgG+ patients were 24, 52 and 84 days, respectively; therefore, we treated four CMV IgG+ CD4+ TEM≥16% patients receiving αPD-1/αCTLA-4 therapy with prophylactic valganciclovir for between 4 and 23 weeks (Fig. 9a). Two of these patients registered mild, transient transaminitis that resolved without treatment, so were not diagnosed with hepatitis. Hence, we observed no hepatitis in the four valganciclovir-treated patients, whereas 15 of 17 (88.2%) CMV IgG+ CD4+ TEM≥16% patients treated with αPD-1/αCTLA-4 and no valganciclovir prophylaxis developed clinical hepatitis (Fig. 9b). To us, these four cases are consistent with the idea that CMV plays an important aetiological role in development of hepatitis after αPD-1/αCTLA-4 therapy in a specific subset of patients.Fig. 9 Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis.
a Heatmaps showing peak values of AST, ALT and bilirubin expressed as multiples of sex-adjusted upper limit of normal ranges. Fifteen of 17 (88.2%) patients classified as CMV IgG+ CD4+ TEM≥16% at baseline subsequently developed hepatitis. In contrast, 4 of 4 CMV IgG+ CD4+ TEM≥16% patients treated with 900 mg/day prophylactic valganciclovir remained hepatitis free. b In four initial cases, prophylactic valganciclovir prevented development of hepatitis (n = 21; F.E.).
Discussion
Our study seeks to explain why a subset of patients with advanced melanoma is predisposed to hepatitis following immune checkpoint blockade. In our model, metastatic disease promotes compartmentalised CMV reactivation in latently infected individuals, possibly triggered by an unknown winter virus infection; in turn, CMV stimulates expansion of CD4+ TEM cells prior to immunotherapy. When αPD-1/αCTLA-4 therapy is given, these TEM cells might inflict liver injury directly or promote bystander T cell responses. We propose CMV-driven T cell responses are a single, but salient example of a general mechanism responsible for hepatitis after checkpoint blockade because other viruses or toxic agents could also drive chronic CD4+ T cell activation before therapy. We speculate anti-viral immunity might also explain predisposition to other adverse reactions following αPD-1/αCTLA-4 therapy, such as colitis or pneumonitis37. The remarkable overlap between organs affected by tissue-invasive CMV disease and those susceptible to immune-related adverse reactions has not escaped our attention38,39.
Being able to identify patients predisposed to hepatitis opens various possibilities for avoiding or preventing treatment-related hepatitis40. Three of four CD4+ TEM≥21% patients assigned to αPD-1 monotherapy instead of αPD-1/αCTLA-4-treatment did not develop hepatitis as predicted; therefore, baseline CD4+ TEM expansion could be taken as a relative contraindication to dual therapy. However, a more promising strategy is to suppress occult CMV reactivation. In our study, valganciclovir prophylaxis apparently prevented hepatitis in four of four CMV IgG+ CD4+ TEM≥16% patients. This approach must be refined in terms of dosing and duration of anti-viral therapy in randomised, controlled clinical trials, but could potentially achieve the superior outcomes of αPD-1/αCTLA-4 dual therapy over αPD-1 monotherapy with fewer complications.
Because baseline CD4+ TEM expansion was observed in patients with metastatic disease, but not in patients with fully resected melanoma, it is possible that disseminated melanoma promotes low-level CMV reactivation, perhaps through compromised T cell immunity, which then stimulates virus-specific CD4+ T cell expansion. The prominent association between CD4+ TEM expansion and CMV (in contrast to other herpesgroup virus infections) might simply reflect differences in tissue tropism and, we speculate, the capacity of compartmentalised CMV reactivation in liver to drive especially strong T cell responses. Seasonal variation in the incidence of CD4+ TEMhigh cases suggests that environmental factors influence expansion and contraction of the CD4+ TEM cell pool41,42. In particular, we suspect common winter viruses somehow promote CMV reactivation in liver.
Chronic, low-level exposure to viral antigens preferentially expands TEM over TCM43–49, so CMV-reactive CD4+ T cell expansion might be sustained by very little CMV replication. On-going T cell reactions against CMV in CD4+ TEMhigh patients are likely to suppress CMV replication almost completely. Our inability to detect CMV in baseline serum samples from CD4+ TEMhigh patients or liver biopsies from patients with high-grade hepatitis is a challenge for our theory; however, it may simply be beyond our technical capability to detect very low levels of compartmentalised viral reactivation. In our view, the strong correlation between CMV-specific immunity and development of hepatitis, as well as the apparent effectiveness of valganciclovir, suggests a causal role for CMV in the aetiology of αPD-1/αCTLA-4-related hepatitis.
We do not presently know whether CMV-specific CD4+ TEM cells inflict liver injury directly or provoke bystander T cell responses50. Administration of αPD-1 or αCTLA-4 has been associated with CMV reactivation in colon, so it is probable that CMV also reactivates in liver during dual therapy51. In two patients with high-grade hepatitis, we observed liver inflammation subsided immediately after starting valganciclovir. In our view, the likely presence of viral antigen and apparent responsiveness to valganciclovir is consistent with a direct pathological effect of CMV-specific T cells, although we accept this will be hard to prove in patients.
Better understanding the contribution of anti-viral T cell immunity to checkpoint blockade-related adverse reactions leads us to unexpected solutions for preventing serious complications of cancer immunotherapy. From a clinical perspective, the immunological mechanisms described illustrate how patients’ medical histories, especially prior exposure to pathogens, impact their experience of cancer and response to therapy.
Methods
Study approval and patient management
This study involving human research participants was performed in accordance with the Declaration of Helsinki and all applicable German and European laws and ethical standards. Specifically, specimens were obtained from patients with Stage III or IV melanoma participating in a single-centre observational clinical trial authorised by the Ethics Committee of the University of Regensburg (approval 16-101-0125) and registered with clinicaltrials.gov (NCT04158544). All participants gave full, informed written consent. The first reported patient was recruited in October 2016 and the last reported patient was recruited in July 2020. Patients received standard-of-care treatment according to local guidelines (Fig. 1a). Stage IV patients with unresectable metastatic disease who received first- or second-line checkpoint inhibitor therapy were initially treated with Nivolumab (αPD-1; Bristol-Myers Squibb) and Ipilimumab (αCTLA-4; Bristol-Myers Squibb) for four cycles, and thereafter with Nivolumab maintenance therapy (3 mg/kg at 3-week intervals). Those patients with complete resection of Stage III melanoma who received adjuvant first-line checkpoint inhibitor therapy were treated for up to 1 year with Pembrolizumab (αPD-1; MSD) or Nivolumab.
Clinical flow cytometry
Detailed step-by-step protocols for preparation and analysis (including specimen gating strategies) of clinical samples by flow cytometry are available through Protocol Exchange52. In brief, peripheral blood samples were collected into ethylenediaminetetraacetic acid (EDTA)-vacutainers by venepuncture and then delivered to the immune monitoring laboratory at ambient temperature. Pre-analytical samples were stored for up to 4 h at 4 °C until processing. Whole blood was stained with DuraClone reagents (Duraclone IM Phenotyping Basic Tube, B53309; Duraclone IM T cell Subsets Tube, B53328; Duraclone IM TCRs Tube, B53340; Duraclone IM Treg Tube, B53346; Duraclone IM B cells Tube, B53318; Duraclone IM Dendritic Cells Tube, B53351; all from Beckman Coulter, Krefeld, Germany). Data were recorded with a NaviosTM cytometer running Cytometry List Mode Data Acquisition and Analysis Software version 1.3 (Beckman Coulter). Blinded analyses were performed by an experienced operator using Kaluza version 2.1 according to gating strategies illustrated in Supplementary Figs. 2–8.
Detection of CMV-reactive T cells by flow cytometry
Detailed step-by-step protocols are available through Protocol Exchange53. Briefly, frozen PBMC from patients were thawed and resuspended in RPMI medium (ThermoFisher, Schwerte, Germany) supplemented with 5% heat-inactivated pooled, male-only human AB serum (ZKT Tübingen, Germany), 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mM Glutamax (ThermoFisher). Cells were plated in 96-well round-bottom plates at 1 × 106 cells in 150 µl/well then incubated at 37 °C with 5% CO2. After 6 h, cultures were stimulated with 5 µg/ml CMV Lysate (Origene) and αCD28/αCD49 for 18 h. In some conditions, cultures were treated with neutralising monoclonal antibodies against PD-1 (MAB10864, R&D) plus CTLA‐4 (MAB3254, R&D) at 5 µg/ml each or mouse IgG1 isotype control (MAB002, R&D) at a final concentration of 10 µg/ml. During the last 4 h of cell culture, protein secretion was blocked with Protein Transport Inhibitor Cocktail (ThermoFisher) containing Brefeldin A und Monensin. Cytokine production was then assessed by flow cytometry. Dead cells were excluded with ViaKrome-808 Fixable Viability Dye (Beckman Coulter). Staining was performed in Cell Staining Buffer (BioLegend) with 10% FcR Block (Miltenyi). Cells were fixed and permeabilised using the eBioscience IC Fixation Buffer and Permeabilization Buffer (eBiosciences, ThermoFisher). Data were recorded with a Cytoflex LXTM cytometer running CytoExpert Software (Beckman Coulter) and analysed using Kaluza version 2.1 (Beckman Coulter) according to the gating strategy shown in Supplementary Fig. 11.
18F-FDG PET/CT imaging
Hepatic glucose metabolism as a measure of liver inflammation34 was analysed retrospectively in all 32 patients who underwent pretreatment 18F-FDG positron emission tomography and computed tomography (PET-CT) imaging as part of routine tumour staging shortly before starting immunotherapy. After overnight fasting, whole-body PET acquisitions covering at least the trunk were started 60–90 min after i.v. injection of 18F-FDG (3 MBq per kg body weight) on a Biograph Sensation 16 LSO or Biograph mCT40 Flow PET/CT scanner (both Siemens Healthcare, Germany) and lasted 18–24 min depending on patient size. The same area was covered by a low-dose CT scan (tube current <50 mAs, tube voltage 120 kV) if no contrast agents were used. Otherwise 130 ml of AccupaqueTM 300 (GE Healthcare) was applied as intravenous contrast agent with consecutive full-dose CT acquisition (120 kV, <100 mAs). PET images (slice thickness 5 mm) were corrected for random coincidences, decay, scatter, and attenuation and reconstructed iteratively using vendor parameter presets. PET and CT images were checked for breathing artifacts and scaled to standardised uptake values (SUV). SUVmean Blood was measured in a thread-like region-of-interest (ROI) manually set into the aorta and SUVmean Liver in a spherical ROI in the right liver lobe using the program ROVER (Version v3.0.35, Helmholtz-Zentrum Dresden-Rossendorf, Germany). SUR was calculated as with correction for the distribution time T of 18F-FDG to the reference time T0 of 75 min post injection54: SUR = (T0/T) × (SUVmean liver / SUVmean blood).
Routine clinical investigations
Routine biochemical and haematological investigations were performed by an in-house accredited diagnostic laboratory (Institute of Clinical Chemistry and Laboratory Medicine, UKR). Virological investigations were conducted by an in-house accredited laboratory (Institute of Clinical Microbiology and Hygiene, UKR) following routine diagnostic procedures. CMV-reactive T cells were quantified by IFN-γ ELISPOT (Lophius, Germany) according to the manufacturer’s instructions in an accredited laboratory (UKR).
Statistics, data transformations and visualisation
Significance tests and curve-fitting were performed with GraphPad Prism 6.04 (GraphPad Software, Inc., La Jolla, USA) or SPSS® version 25 (IBM Analytics, New York, USA). As indicated, data were analysed using a two-tailed Mann–Whitney (M.W.) test, two-tailed Fisher’s exact test (F.E.), D’Agostino & Pearson’s normality test (K2), one-way or two-way ANOVA, two-tailed t-tests, log-rank survival analysis, receiver-operator characteristic (ROC) analysis or calculating pairwise Pearson correlations (R2). Where stated in the figure legends, p-values were adjusted for multiple comparison using Benjamini–Hochberg (B.H.) correction or Bonferroni correction, but otherwise no adjustment was made.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Peer Review File
Reporting Summary
Source data
Source Data
Supplementary information
The online version contains supplementary material available at 10.1038/s41467-021-21572-y.
Acknowledgements
The authors gratefully acknowledge the financial support of Bristol-Myers Squibb and the BMS Foundation (Award FA-19-009) in the form of unrestricted research grants. This study was partly supported by grants from the German Research Foundation to S.H. (DFG HA 8481/1-1) and J.A.H. (DFG HU 1838/1-1; DFG HU 1838/2-1). L.C. is a Marie Skłodowska-Curie Research Fellow affiliated with INsTRuCT and receives funding from the European Union’s Horizon 2020 research and innovation programme (Award 860003). The authors thank Dr. Michael Kapinsky of Beckman Coulter GmbH for advice and support with clinical flow cytometry. The authors also thank Prof. Tobias Pukrop and staff of the Interdisciplinary Center for drug Tumor Therapy (ICT) for supporting collection of clinical samples. This work would not have been possible without the outstanding technical support of Erika Ostermeier, Marina Sorokina, Veronika Menath, Anke Hofmann and Joachim Schweimer.
Author contributions
J.A.H. designed the immune monitoring studies and other experiments, analysed the results and wrote the manuscript; K.K. organised and performed immune monitoring studies; P.R. designed and performed the experiments; J.J.W., J.K. and B.S. performed the virological analyses; K.E. provided expert histopathological descriptions; M.S., L.B. and D.H. performed the radiological and molecular imaging analyses; G.G., F.Z. and R.S. provided expert statistical and bioinformatics advice; L.C. quality-checked the manuscript; C.B. and R.B. were responsible for the routine clinical laboratory analyses; M.M. and K.D. provided the biological samples; H.L.S. and F.B. performed the experiments; H.J.S. provided infrastructural support; E.K.G., J.M.W. and S.H. provided material support, patient samples and critical feedback throughout the project. All authors approved the final version of the manuscript.
Data availability
Data supporting the findings of this study are available within the article and its Supplementary information files, or are available from the corresponding author subject to legal restrictions governing use of personal information. Source data are provided with this paper.
Competing interests
S.H. declares he has received consulting fees and speaker’s honoraria from BMS and Merck Sharp & Dohme (MSD). All other authors declare no competing interests.
Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BINIMETINIB, ENCORAFENIB, IPILIMUMAB, NIVOLUMAB, PREDNISOLONE | DrugsGivenReaction | CC BY | 33664251 | 19,620,963 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis.
Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.
Introduction
Treatment with anti-programmed cell death protein-1 (αPD-1) alone or combined with anti-cytotoxic T-lymphocyte-associated protein 4 (αCTLA-4) has greatly improved the prognosis of metastatic melanoma with a substantial fraction of patients achieving long-lasting partial or complete clinical responses1–6. The principal limitation of αPD-1/αCTLA-4 dual therapy is the relatively high rate of immune-related complications, which commonly include colitis, hepatitis and thyroiditis, but may also include pneumonitis, myocarditis and encephalitis7,8. Such adverse events range from mild reactions to life-threatening presentations, but are nevertheless clinically significant incidents that influence patient management9,10. Avoidance of complications has led to a somewhat complicated treatment decision-making process (Fig. 1a) that seeks to balance individual risk and capacity to tolerate adverse reactions against the superior clinical responses achieved with dual αPD-1/αCTLA-4 therapy over αPD-1 monotherapy11–13.Fig. 1 Individual predisposition to hepatitis after αPD-1/αCTLA-4 treatment.
a Individualised treatment of melanoma is guided by tumour staging, presence of B-RAF mutations and fitness-for-toxicity. b Colitis, hepatitis and thyroiditis are common immune-related complications of dual therapy with Nivolumab plus Ipilimumab; 31.4% of patients experienced two or more of these immune-related adverse reactions (n = 89). c Colitis, hepatitis and thyroiditis occurred independently and were not significantly associated with clinical response (n = 89; F.E). d–h Patients who developed hepatitis of any grade following dual therapy lacked biochemical signs of liver inflammation before treatment. In particular, no clinically meaningful differences in plasma levels of d aspartate transaminase (AST; n = 87; M.W.; Bonferroni-corrected p-value, m = 5), e alanine transaminase (ALT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), f gamma glutamyl transaminase (γ-GT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), g total bilirubin (n = 87; M.W.; Bonferroni-corrected p-value, m = 5), or h C-reactive protein (CRP; n = 85; M.W.; Bonferroni-corrected p-value, m = 5) were observed between patients who developed hepatitis and those who did not. Median values are indicated by a red line. i, j Biochemical markers of tumour burden were not different between patients who developed hepatitis and those who did not. i Pre-treatment levels of lactate dehydrogenase (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. j Pre-treatment levels of protein S100 (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). k–m No association was observed between seropositivity for k hepatitis B virus core antigen (HBcAg; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), l hepatitis C virus (HCV; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), or m hepatitis E virus (HEV; n = 67; F.E.; Bonferroni-corrected p-value, m = 3) and development of hepatitis following dual therapy. n No association was observed between rounds of αPD-1/αCTLA-4 administered and development of hepatitis (n = 89; M.W.).
Our aetiological understanding of colitis, hepatitis and thyroiditis caused by immune checkpoint blockade remains incomplete14; however, these treatment-related conditions are clearly different from known autoimmune diseases15,16. Such adverse reactions are usually attributed to generalised dysregulation of T cells17,18 or autoantibodies15. Here, we explore a different view—namely, that individual patients are predisposed to particular treatment-related complications by virtue of pathogen-specific memory T cells present in their repertoire before immune checkpoint blockade is given.
Cytomegalovirus (CMV) seroprevalance amongst European adults is over 50%. Primary CMV infection usually presents during young adulthood as an acute febrile illness, after which life-long latency is established. The exact sites and mechanisms of CMV latency are not fully resolved, but myelomonocytic cells in blood and tissues are major reservoirs19. CMV reactivation characteristically follows immune compromise caused by immunosuppressive therapy or other viral infections20. Clinical manifestations of CMV reactivation are variable, ranging from classic febrile illness to tissue-invasive disease presenting as colitis, hepatitis, pneumonitis or encephalitis21. Reactivation of CMV causes cellular injury through the cytopathic effect of viral replication, but more conspicuously through triggering T cell immunity. Pneumonitis in transplant recipients illustrates how CMV-reactive T cells provoke extensive, life-threatening inflammation despite low-level viral replication22. Even in anatomical locations from which T cells are normally excluded, such as the retina, T cell-mediated responses significantly contribute to CMV-related disease. Thus, low-level and compartmentalised reactivation of CMV can be responsible for serious acute immunopathology in humans23–25.
Cycles of CMV latency and reactivation lead to a now well-recognised phenomenon of memory inflation, which is typified by failure of primed CMV-specific CD8+ T cell populations to contract and give rise to central memory T cells26. Instead, a dominant pool of effector memory CD8+ T cells that does not become functionally exhausted is maintained27. Such inflationary CD8+ T cells achieve high frequencies over time, sustained through repetitive stimulation by viral reactivation or long-term persistence of viral antigens28. Memory inflation is described as an exclusive feature of CD8+ effector T cell responses, although durable expansion of CMV-specific CD4+ T cells can occur in transplant recipients29.
This study identifies pre-therapy expansion of CD4+ effector memory T cells (TEM) in CMV-infected patients with metastatic melanoma as a prognostic marker of αPD-1/αCTLA-4-related hepatitis. Opting for αPD-1 monotherapy or prophylactic valganciclovir in CMV IgG+ patients with unresectable metastatic disease and pre-treatment expansion of CD4+ TEM cells reduces their risk of hepatitis. We conclude that sub-clinical reactivation of CMV plays a previously unsuspected role in the immunopathogenesis of αPD-1/αCTLA-4-related hepatitis in a subgroup of patients.
Results
Clinical features do not predict αPD-1/αCTLA-4-related hepatitis
If immune-related complications of αPD-1/αCTLA-4 therapy resulted solely from treatment-induced immunological effects30,31, we might expect hepatitis, colitis and thyroiditis to coincide often32 (Fig. 1b). However, no such associations were found in a cohort of 89 patients with metastatic melanoma treated with αPD-1/αCTLA-4 dual therapy (Fig. 1c, Supplementary Fig. 1 and Supplementary Tables 1–3). This raises the possibility that some individuals are predisposed to particular adverse reactions.
In this study, we focused on factors that predispose to αPD-1/αCTLA-4-related hepatitis. Except for patients who developed hepatitis being generally younger (Supplementary Table 4) no associations were found between incidence of hepatitis and pre-treatment clinical variables (Supplementary Tables 4 and 5). Conventional biochemical markers of liver dysfunction, systemic inflammation or tumour burden did not discriminate between patients who did or did not develop hepatitis (Fig. 1d–j). We found no associations between incidence of hepatitis and seropositivity for hepatitis B virus (HBV), hepatitis C virus (HCV) or hepatitis E virus (HEV; Fig. 1k–m). Incidence of hepatitis was not greater with more rounds of αPD-1/αCTLA-4 therapy; in fact, as immune-related complications are reason to withhold treatment, patients who developed hepatitis tended to receive fewer rounds of αPD-1/αCTLA-4 (Fig. 1n). Autoimmune hepatitis-related autoantibodies were not associated with risk of hepatitis (Supplementary Table 6). In short, case history and routine clinical investigations did not predict hepatitis after dual therapy in our study cohort.
CD4+ TEM cell expansion predicts αPD-1/αCTLA-4-related hepatitis
We next profiled circulating leucocyte subsets immediately prior to start of dual therapy in a training set of n = 44 patients with unresectable metastatic melanoma (Supplementary Figs. 2–8). Comparing the frequency of 50 principal leucocyte subsets between patients who subsequently did (n = 18) or did not (n = 26) develop hepatitis revealed significant over-representation of CD4+ TEM cells associated with hepatitis (Fig. 2a, b). This observation was confirmed in a validation set (n = 45) of similar patients (Fig. 2c). Baseline expansion of CD4+ TEM cells was a fair discriminator (AUROC = 0.706) of patients who did or did not later develop hepatitis in the validation set (Fig. 2d). Strikingly, CD4+ TEM cell frequencies in all patients with completely resected disease were normally distributed with no extreme cases of baseline CD4+ TEM cell expansion, allowing us to set a threshold below which 99% of patients should fall (Fig. 2e). Applying this stringent cut-off to our validation cohort of patients with unresectable metastatic disease (Fig. 2f) allowed us to correctly predict hepatitis in 6 of 6 patients with CD4+ TEM≥21% (specificity = 100%) and correctly identify 6 of 20 patients who developed hepatitis (sensitivity = 30.0%). CD4+ TEM≥21% patients were not predisposed to colitis (Fig. 2g), thyroiditis or superior clinical responses to therapy (Supplementary Table 7). Hepatitis was not more severe in CD4+ TEM≥21% patients compared to CD4+ TEM<21% patients (Fig. 2h) and no difference in time-to-first presentation was observed (Fig. 2i). Hence, baseline CD4+ TEM expansion is a specific, but relatively insensitive prognostic marker of individuals who are predisposed to hepatitis after αPD-1/αCTLA-4 therapy. Owing to its low sensitivity, classifying patients as CD4+ TEM<21% has limited clinical utility; however, specifically identifying cases at high-risk of hepatitis before treatment is useful from a research perspective because we can then prospectively study the immunological basis of their predisposition.Fig. 2 Circulating CD4+ T effector memory cell frequency predicts hepatitis after Nivolumab plus Ipilimumab treatment.
a Peripheral blood samples were collected from melanoma patients with metastatic disease receiving αPD-1/αCTLA-4 therapy immediately before administration of the first dose (n = 89). Leucocyte subsets differentially represented in patients with or without hepatitis were identified in a randomly assigned training set (B.H.-corrected t-tests; n = 44; m = 50; FDR = 0.25). Red dots indicate significantly differently represented subsets. Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. b CD4+ TEM % in training set patients with or without treatment-related hepatitis (n = 44; M.W.). Median values are indicated by a red line. c CD4+ TEM % in validation set patients with or without treatment-related hepatitis (n = 45; M.W.). d ROC analysis of CD4+ TEM % as a discriminatory marker for treatment-related hepatitis in the validation set (n = 45). e Comparison of the bimodal distribution of CD4+ TEM % in patients with unresectable metastatic disease (n = 107) and the normal distribution (n = 49; K2 = 2.79; p = 0.248) of CD4+ TEM % in patients with completely resected tumours. A cut-off of CD4+ TEM ≥ 21% was set (indicated by a dashed red line) below which 99% of completely resected tumour cases should fall. Four pink points represent CD4+ TEM≥21% patients with metastatic disease who were electively treated with αPD-1 monotherapy. f In the validation set, 68.9% patients were correctly classified using a cut-off of CD4+ TEM ≥ 21 %, whereas 55.6% were correctly classified under the no-information model (n = 45; F.E.). g CD4+ TEM ≥ 21 % is not a marker of predisposition to αPD-1/αCTLA-4-related colitis (n = 89; F.E.). h CD4+ TEM≥21% patients did not experience more severe hepatitis than CD4+ TEM<21% patients (n = 38; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. i Time-to-first presentation of hepatitis was not different between CD4+ TEM≥21% (n = 12) and TEM<21% (n = 26) patients (log-rank). j Twelve of 12 patients with unresectable metastatic melanoma and CD4+ TEM ≥ 21% developed hepatitis after αPD-1/αCTLA-4 dual therapy. By contrast, 3 of 4 CD4+ TEM≥21% patients treated with αPD-1 monotherapy did not develop hepatitis (F.E.; p = 0.007).
Opting for αPD-1 monotherapy reduces risk of hepatitis
Although αPD-1 monotherapy achieves fewer sustained clinical responses in patients with metastatic melanoma, it causes fewer adverse reactions than αPD-1/αCTLA-4 dual therapy1. Therefore, there is a clear rationale for avoiding αPD-1/αCTLA-4 dual therapy in patients at risk of hepatitis. Four CD4+ TEM≥21% patients with metastasic disease presented during our study, but were electively treated with αPD-1 monotherapy (Fig. 2j). Whereas 12 of 12 CD4+ TEM≥21% patients treated with αPD-1/αCTLA-4 dual therapy developed hepatitis, 3 of 4 CD4+ TEM≥21% patients who received αPD-1 monotherapy remained hepatitis free. Reducing the incidence hepatitis by opting for αPD-1 monotherapy hints that CTLA-4 blockade may be mechanistically important for development of hepatitis in CD4+ TEM≥21% patients33.
CD4+ TEM frequency is an independent predictor of hepatitis
We next investigated possible causes of baseline CD4+ TEM expansion. To establish CD4+ TEM expansion as an independent risk factor, we first sought to exclude possible confounding covariables. Baseline CD4+ TEM≥21% was not related to sex, age or body-mass index (Supplementary Table 7 and Fig. 3a, b). No significant correlation was observed between baseline CD4+ TEM % and serum levels of C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT) or total bilirubin (Fig. 3c–g). Because glucose metabolism provides a reliable measure of liver inflammation34, we were able to further rule out liver inflammation prior to therapy as a predisposing cause of CD4+ TEM≥21% hepatitis by estimating hepatic glucose uptake in patients who underwent 18F-fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT studies as part of routine tumour staging shortly before starting immunotherapy (Fig. 3h). This retrospective comparison showed 18F-FDG standard uptake ratios (SURmean liver) were higher in CD4+ TEM<21% patients than CD4+ TEM≥21% patients with hepatitis (Fig. 3i). Therefore, our biochemical and radiological investigations argue against pre-treatment liver inflammation as a common cause for baseline CD4+ TEM expansion and treatment-related hepatitis.Fig. 3 CD4+ TEM frequency is an independent predictor of αPD-1/αCTLA-4-related hepatitis.
a CD4+ TEM % did not correlate with age (n = 89; Pearson). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM % did not correlate with body mass index (n = 89; Pearson). c CD4+ TEM % did not correlate with C-reactive protein (CRP) levels (n = 85; Pearson). d CD4+ TEM % did not correlate with aspartate aminotransferase (AST) levels (n = 87; Pearson). e CD4+ TEM % did not correlate with alanine aminotransferase (AST) levels (n = 89; Pearson). f CD4+ TEM % did not correlate with gamma-glutamyltransferase (γ-GT) levels (n = 89; Pearson). g CD4+ TEM % did not correlate with total bilirubin levels (n = 89; Pearson). h Glucose metabolism measured by 18F-fluoro-2-deoxy-d-glucose (18F-FDG) uptake in PET/CT studies is a quantitative marker of liver inflammation. Calculating standard uptake ratio (SURmean Liver) allows accurate quantification of 18F-FDG uptake in liver by correcting for differential clearance of tracer from blood and liver parenchyma. Higher SURmean Liver values indicate more severe inflammation. T0 = reference time point at 75 min post-injection and T = actual scan time. i SURmean Liver was lower in CD4+ TEM≥21% patients than CD4+ TEM<21% patients who developed hepatitis indicating less inflammation at baseline in the CD4+ TEM≥21% subgroup (n = 28; Pearson). j CD4+ TEM≥21% was not associated with the number of organs containing one or more metastases ≥1.5 cm in diameter (n = 103; F.E.). k CD4+ TEM≥21% was not associated with the presence of hepatic metastases (n = 103; F.E.). l CD4+ TEM % did not correlate with lactate dehydrogenase (LDH) levels (n = 88; Pearson). m CD4+ TEM % did not correlate with protein S100 levels (n = 88; Pearson). n CD4+ TEM≥21% was not associated with any prior therapy (n = 89; F.E.).
Because CD4+ TEM expansion is principally a feature of metastatic melanoma (Fig. 2e), we next asked whether CD4+ TEM% was somehow associated with tumour burden. No relationship was found between CD4+ TEM% and the number of organs containing metastases, presence of hepatic metastases or serum lactate dehydrogenase (LDH) and protein-S100 serum levels (Fig. 3j–m and Supplementary Table 7). There was a tendency for CD4+ TEM≥21% patients to have received previous therapy of any type (including BRAFi/MEKi or Talimogen laherparepvec) but besides implying a longer disease course before starting dual therapy, we see no mechanistic interpretation because these drugs share no common pharmacological action (Fig. 3n). In short, we found no obvious clinical association to explain the predisposition of CD4+ TEM≥21% patients to hepatitis.
CD4+ TEM cell expansion is associated with chronic T cell activation
Although CD4+ T cell counts were not different between CD4+ TEM<21% and CD4+ TEM≥21% patients (Supplementary Table 7), there were significantly fewer circulating naïve T cells in CD4+ TEM≥21% patients (Fig. 4a). This reduction was complemented by increased absolute numbers of CD4+ TEM and TEMRA cells (Fig. 4b, c) whereas central memory T cell (TCM) counts tended to be lower in CD4+ TEM≥21% patients (Fig. 4d). We next defined other leucocyte subsets that correlated with CD4+ TEM % in both our training and validation cohorts (Fig. 4e). Most covariant populations were T cells, particularly CD4+ T cell subsets. Changes in the CD4+ T cell compartment of TEM≥21% patients were consistent with chronic activation, particularly downregulation of CD27 and upregulation of CD57, HLA-DR and CD279 expression (Fig. 4f–i). Similar differences were detected in CD8+ T cells (Supplementary Fig. 9). Notably, CD4+ TEM≥21% patients tended to have higher frequencies of CD160+ CD244+ exhausted CD8+ T cells than CD4+ TEM<21% patients (Fig. 4j).Fig. 4 CD4+ TEM cell enrichment is associated with chronic activation and increased numbers of effector memory CD4+ T cells.
a–d Increased CD4+ TEM frequency before treatment reflects a decrease in circulating naïve CD4+ T cells and an increase in circulating numbers of CD4+ TEM cells. a Baseline naïve CD4+ T cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 5.2 ⨯ 10−5). b Baseline CD4+ TEM cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 8.0 ⨯ 10−4). c Baseline CD4+ TEMRA cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). d Baseline CD4+ TCM cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. e Pairwise correlations between CD4+ TEM cell frequency and other leucocyte subset frequencies in the training and validation sets (n = 103; Pearson). Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. f Baseline CD27+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.2 ⨯ 10−10). g Baseline CD57+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 2.0 ⨯ 10−9). h Baseline HLA-DR+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.1 ⨯ 10−5). i Baseline CD279+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). j Baseline CD160+ CD244+ CD8+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). k Baseline Torque Teno Virus (TTV) loads. Uninfected patients were censored from analysis (n = 74; M.W.; Bonferroni-corrected p-value, m = 60). Median values are indicated by a red line.
Most adults are persistently infected with Torque Teno Virus (TTV), a non-enveloped, circular, single-stranded DNA virus of the Anellovirus family that causes no apparent disease. T cell immunity controls TTV replication in healthy people, whereas TTV copy number in immunocompromised individuals is increased; therefore, TTV load in plasma is a useful marker of immune competence. Despite accumulating chronically activated and exhausted T cells, TTV load in CD4+ TEM≥21% versus CD4+ TEM<21% patients was not different, implying that CD4+ TEM≥21% patients are not generally immunocompromised (Fig. 4k).
CD4+ TEM cell expansion correlates with immunity to CMV
To briefly summarise, baseline expansion of CD4+ TEM cells identifies a subset of patients with metastasic melanoma who are predisposed to αPD-1/αCTLA-4-related hepatitis. These patients show signs of persistent or recurrent CD4+ and CD8+ T cell responses35, but are otherwise clinically and immunologically unremarkable. It is usually very difficult to isolate factors responsible for such a non-specific immunological picture36. Fortunately, a surprising pattern emerged from our dataset: CD4+ TEM≥21% patients mostly presented between September and February (Fig. 5a). This seasonal influence was apparent over all 4 years of the study, leading us to think that CD4+ TEM expansion might be driven by a pathogen. Active infections with hepatitis viruses, including HBV and HCV, are relative contraindications to αPD-1/αCTLA-4 therapy (Supplementary Table 7), so we were forced to consider possible involvement of other hepatotropic viruses, such as HEV and herpesgroup viruses.Fig. 5 CD4+ TEM cell expansion correlates with immunity to cytomegalovirus.
a Seasonal presentation of CD4+ TEM≥21% patients between 2017 and 2020 (n = 103; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM≥21% status was associated with high serum levels of anti-CMV IgG antibodies (n = 100; F.E.; p = 1.2 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. c CD4+ TEM≥21% status was associated with CMV-reactivity in pp65 ELISPOT (n = 53; F.E.; p = 9.0 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. d Development of hepatitis was associated with CMV-seropositivity and CD4+ TEM≥21% status (n = 89). Median values are indicated by a red line. e ROC analysis showing CD4+ TEM % is a superior discriminator of patients at risk of hepatitis when considering only CMV IgG+ cases as opposed to all cases. f Classification of patients with unresectable metastatic melanoma who did or did not develop αPD-1/αCTLA-4-related hepatitis according to CMV IgG status and baseline CD4+ TEM cell frequency using a revised cut-off of CD4+ TEM ≥ 16%. Red boxes indicate 34 of 40 (85%) cases correctly classified by our model (n = 40; F.E.; p = 1.4 ⨯ 10−5). Green box indicates 2 of 17 (11.7%) cases predicted to develop hepatitis who did not. Pink box indicates 4 of 23 (17.4%) cases predicted not to develop hepatitis who did. Blue box indicates 19 of 49 CMV IgG− patients not considered by our model who developed hepatitis.
Latent CMV infection is prevalent amongst European adults and involves many organs, including liver. Compartmentalised reactivation of CMV infection occurs in immunocompromised individuals and those with concomitant viral upper respiratory tract infections20. In our patients, we found a strong association between serum CMV-specific IgG antibody levels and CD4+ TEM status (Fig. 5b). Furthermore, T cell reactivity against CMV pp65 peptides in an IFN-γ enzyme-linked immunospot (ELISPOT) assay was tightly associated with CD4+ TEM status (Fig. 5c). These results led us to hypothesise a causal relationship between compartmentalised, sub-clinical CMV reactivation in liver and chronic enrichment of CD4+ TEM cells in blood.
Because baseline CD4+ TEM cell expansion was mainly a feature of CMV IgG+ patients (Fig. 5d), we next asked whether incorporating CMV IgG status could improve our predictive model. When considering only CMV IgG+ cases, CD4+ TEM % was a more discriminatory marker of hepatitis (Fig. 5e). Therefore, using our training set filtered for CMV IgG+ cases, we revised our cut-off to CD4+ TEM ≥ 16% in CMV IgG+ cases in order to achieve a better compromise between specificity and sensitivity (Supplementary Fig. 10). The new cut-off performed well in the validation set with a correct classification rate of 81.0% (positive predictive value (PPV) = 85.7% and negative predictive value (NPV) = 78.6%) compared to 42.9% under the no-information model.
For descriptive purposes, we can consider the distribution of patients from the combined training and validation sets according to CMV IgG and CD4+ TEM status (Fig. 5f). Our predictive model explains the occurrence of hepatitis in 34 of 89 (38.2%) of all patients (red boxes). Two of 17 (12%) CMV IgG+ CD4+ TEM≥16% patients (green box) did not develop hepatitis: one of these received four rounds of αPD-1/αCTLA-4 therapy and registered no complications; however, the other received only 1 round of αPD-1/αCTLA-4 before treatment with prednisolone from weeks 2 to 7 for colitis. We speculate 4 of 23 CMV IgG+ CD4+ TEM<16% patients who were incorrectly predicted as hepatitis-negative (pink box) were sampled at an early stage of CD4+ TEM cell expansion and our test was not sensitive enough to discriminate the change. Our model does not explain why 19 of 49 CMV IgG− patients developed hepatitis (blue box) but we believe these represent an aetiologically distinct subset.
CMV-reactive CD4+ T cells are enriched in CD4+ TEMhigh patients
We next asked whether CMV-reactive CD4+ T cells were enriched in patients with baseline CD4+ TEM expansion. Peripheral blood mononuclear cells (PBMC) were stimulated in culture for 18 h with CMV lysates before IFN-γ, TNFα, IL-17, IL-4 and CD69 expression was measured by flow cytometry (Fig. 6a and Supplementary Figs. 11 and 12). To detect hyporesponsive CMV-specific T cells, paired cultures were also stimulated in the presence of neutralising antibodies against PD-1 and CTLA-4. In contrast to CMV IgG− and CMV IgG+ CD4+ TEM<16% patients, we readily detected IFN-γ-producing, CMV-reactive CD4+ T cells in CMV IgG+ CD4+ TEM≥16% patients (Fig. 6b). This difference implies a higher number of circulating IFN-γ-producing, CMV-reactive CD4+ T cells (Fig. 6c). Proportions of CMV-reactive CD4+ T cells expressing IL-17, IL-4 or only TNFα were too low to quantify accurately.Fig. 6 CMV-reactive CD4+ T cells are enriched in patients with CD4+ TEM cell expansion.
CMV-reactive CD4+ T cells in patients with unresectable metastatic melanoma were assayed by in vitro stimulation with CMV lysates (blue boxes). Neutralising antibodies (red hatching) were used to detect T cells unable to respond to CMV antigens owing to expression of PD-1 or CTLA-4. T cell responses were quantified by flow cytometry analysis of cytokine expression. a Example data from a CMV IgG+ CD4+ TEM≥16% patient who developed hepatitis. Gating of live, singlet, IFN-γ-producing CD4+ T cells is illustrated in Supplementary Fig. 11. b Frequencies of IFN-γ-producing CD4+ T cells in patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers. c Absolute numbers of circulating IFN-γ-producing CD4+ T cells patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers.
Valganciclovir reverses αPD-1/αCTLA-4-related hepatitis
Strong associations between T cell immunity against CMV, expansion of CD4+ TEM and risk of treatment-related hepatitis imply an underlying pathogenic mechanism; however, to demonstrate a causal relationship, we needed to establish that inhibiting CMV replication was effective in treating or preventing hepatitis. Valganciclovir is an anti-viral agent licensed for therapy and prophylaxis of CMV infections in immunocompromised patients. It is a widely used and safe drug with a well-known and broadly acceptable profile of adverse effects. Therefore, we next gave valganciclovir treatment to two patients with αPD-1/αCTLA-4-related hepatitis.
The first patient was a comparatively fit 54-year-old man with a new diagnosis of metastatic melanoma (Fig. 7a). Staging CT revealed multiple lung and bone metastases, but no metastasis to liver or lymph nodes. At baseline, the patient was CMV-IgG+ and CD4+ TEM = 18.7% (Fig. 7b). Nivolumab plus Ipilimumab were given at 0, 3 and 6 weeks. A fourth round of αPD-1/αCTLA-4 at week 9 was omitted owing to joint pain and the patient received two rounds of Denosumab (αRANKL). Nivolumab monotherapy was administered in weeks 12, 16, 20 and 24. Staging CT at week 14 showed a partial clinical response with significant regression of pulmonary metastases; hence, checkpoint blockade was of clear clinical benefit.Fig. 7 Case 1: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 54-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction, withdrawal and re-introduction of valganciclovir treatment. c The patient presented at the end of week 40 with recrudescent hepatitis and was treated with 900 mg/day valganciclovir for 2 days prior to liver biopsy. Histopathological image of the liver biopsy (H&E staining; scale bar 500 µm). d Generally, the liver parenchyma appeared normal (H&E staining; scale bar 100 µm). e Only a few lymphocytes and sparse necrotic hepatocytes were observed in portal areas with small bile plugs (arrows) with no signs of hepatitis (H&E staining; scale bar 100 µm).
The patient received a dose of αPD-1 monotherapy in week 32. Four weeks later, he presented in clinic with grade 4 hepatitis. Strong reactions against pp65 and IE-1 peptides were measured by ELISPOT. Accordingly, the patient was treated with 900 mg/day valganciclovir plus prednisolone. Liver function tests (LFTs) returned to normal, so over the subsequent 2 weeks, prednisolone was weaned and then valganciclovir was withdrawn. Seven days later, the patient returned to clinic with deranged LFTs. Valganciclovir and prednisolone were both reinstated, leading to a rapid normalisation of LFTs. Two days later, a for-cause liver biopsy was performed (Fig. 7c–e). The tissue was essentially normal, although a few dying hepatocytes and isolated lymphocytes were observed in the portal areas. Immunohistochemical staining for CMV and nested CMV PCR from fixed biopsy material were negative. The patient remained clinically stable for 9 days, so he was again weaned from prednisolone by the start of week 43; however, on this occasion, 900 mg/day valganciclovir treatment was continued. After complete withdrawal of prednisolone, while still receiving valganciclovir, the patient’s LFTs remained stable for a further 4 weeks. At the start of week 47, valganciclovir was withdrawn for a second time. Subsequently, the patient did not develop hepatitis and required no further steroids. The patient received further doses of αPD-1 monotherapy in weeks 54 and 58 without signs of recurrent liver injury. To us, this suggests the T cell antigens driving hepatitis in this patient were absent after valganciclovir treatment. In our clinical opinion, despite the absence of detectable virus, the patient’s fast recovery and unusual relapse of hepatitis are best explained by introduction, withdrawal and reintroduction of valganciclovir.
The second patient was a 49-year-old man who had an uncomplicated first year after αPD-1/αCTLA-4 and had been receiving Encorafenib/Binimetinib therapy for 7 weeks when he developed hepatitis in week 67 (Fig. 8a, b). Hepatitis failed to resolve despite withdrawal of B-RAFi/MEKi and escalating doses of prednisolone. 900 mg/day valganciclovir was introduced at the start of week 72 and a for-cause biopsy was performed on the same day (Fig. 8b). Four days later, the patient started a course of 1 mg/day mycophenolate mofetil. Strikingly, AST, ALT and γ-GT levels declined consistently from the day after valganciclovir was given, although total bilirubin continued to rise. Starting valganciclovir treatment appeared to be temporally related to increased reactivity in CMV IE-1 ELISPOT and a small decline in CD4+ TEM frequency.Fig. 8 Case 2: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 49-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction of valganciclovir treatment. c Histopathological image of a liver biopsy taken at the start of week 72 showing signs consistent with drug toxicity, autoimmunity or viral infection (H&E staining; scale bar 500 µm). d Extensive centrilobular necrosis (arrows) involving 30–40% of hepatocytes was observed (H&E staining; scale bar 100 µm). e Dense inflammatory infiltration of lymphocytes, eosinophils and neutrophils was seen in portal areas (H&E staining; scale bar 100 µm).
Liver biopsy revealed dense infiltration by lymphocytes, eosinophils and neutrophils with an accompanying ductal reaction (Fig. 8c–e). Extensive centrilobular hepatocyte necrosis was observed, which was also associated with inflammatory infiltration. These histopathological signs of significant liver damage could have been consistent with autoimmunity or viral infection. Both histological staining for CMV and CMV PCR from fixed biopsy material were negative. Although we were unable to detect virus, it is our clinical impression that markers of liver damage responded to valganciclovir treatment.
Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis
We next asked whether valganciclovir prophylaxis could prevent αPD-1/αCTLA-4-related hepatitis in predisposed individuals. The 50th, 75th and 90th percentiles of time-to-hepatitis in CMV-IgG+ patients were 24, 52 and 84 days, respectively; therefore, we treated four CMV IgG+ CD4+ TEM≥16% patients receiving αPD-1/αCTLA-4 therapy with prophylactic valganciclovir for between 4 and 23 weeks (Fig. 9a). Two of these patients registered mild, transient transaminitis that resolved without treatment, so were not diagnosed with hepatitis. Hence, we observed no hepatitis in the four valganciclovir-treated patients, whereas 15 of 17 (88.2%) CMV IgG+ CD4+ TEM≥16% patients treated with αPD-1/αCTLA-4 and no valganciclovir prophylaxis developed clinical hepatitis (Fig. 9b). To us, these four cases are consistent with the idea that CMV plays an important aetiological role in development of hepatitis after αPD-1/αCTLA-4 therapy in a specific subset of patients.Fig. 9 Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis.
a Heatmaps showing peak values of AST, ALT and bilirubin expressed as multiples of sex-adjusted upper limit of normal ranges. Fifteen of 17 (88.2%) patients classified as CMV IgG+ CD4+ TEM≥16% at baseline subsequently developed hepatitis. In contrast, 4 of 4 CMV IgG+ CD4+ TEM≥16% patients treated with 900 mg/day prophylactic valganciclovir remained hepatitis free. b In four initial cases, prophylactic valganciclovir prevented development of hepatitis (n = 21; F.E.).
Discussion
Our study seeks to explain why a subset of patients with advanced melanoma is predisposed to hepatitis following immune checkpoint blockade. In our model, metastatic disease promotes compartmentalised CMV reactivation in latently infected individuals, possibly triggered by an unknown winter virus infection; in turn, CMV stimulates expansion of CD4+ TEM cells prior to immunotherapy. When αPD-1/αCTLA-4 therapy is given, these TEM cells might inflict liver injury directly or promote bystander T cell responses. We propose CMV-driven T cell responses are a single, but salient example of a general mechanism responsible for hepatitis after checkpoint blockade because other viruses or toxic agents could also drive chronic CD4+ T cell activation before therapy. We speculate anti-viral immunity might also explain predisposition to other adverse reactions following αPD-1/αCTLA-4 therapy, such as colitis or pneumonitis37. The remarkable overlap between organs affected by tissue-invasive CMV disease and those susceptible to immune-related adverse reactions has not escaped our attention38,39.
Being able to identify patients predisposed to hepatitis opens various possibilities for avoiding or preventing treatment-related hepatitis40. Three of four CD4+ TEM≥21% patients assigned to αPD-1 monotherapy instead of αPD-1/αCTLA-4-treatment did not develop hepatitis as predicted; therefore, baseline CD4+ TEM expansion could be taken as a relative contraindication to dual therapy. However, a more promising strategy is to suppress occult CMV reactivation. In our study, valganciclovir prophylaxis apparently prevented hepatitis in four of four CMV IgG+ CD4+ TEM≥16% patients. This approach must be refined in terms of dosing and duration of anti-viral therapy in randomised, controlled clinical trials, but could potentially achieve the superior outcomes of αPD-1/αCTLA-4 dual therapy over αPD-1 monotherapy with fewer complications.
Because baseline CD4+ TEM expansion was observed in patients with metastatic disease, but not in patients with fully resected melanoma, it is possible that disseminated melanoma promotes low-level CMV reactivation, perhaps through compromised T cell immunity, which then stimulates virus-specific CD4+ T cell expansion. The prominent association between CD4+ TEM expansion and CMV (in contrast to other herpesgroup virus infections) might simply reflect differences in tissue tropism and, we speculate, the capacity of compartmentalised CMV reactivation in liver to drive especially strong T cell responses. Seasonal variation in the incidence of CD4+ TEMhigh cases suggests that environmental factors influence expansion and contraction of the CD4+ TEM cell pool41,42. In particular, we suspect common winter viruses somehow promote CMV reactivation in liver.
Chronic, low-level exposure to viral antigens preferentially expands TEM over TCM43–49, so CMV-reactive CD4+ T cell expansion might be sustained by very little CMV replication. On-going T cell reactions against CMV in CD4+ TEMhigh patients are likely to suppress CMV replication almost completely. Our inability to detect CMV in baseline serum samples from CD4+ TEMhigh patients or liver biopsies from patients with high-grade hepatitis is a challenge for our theory; however, it may simply be beyond our technical capability to detect very low levels of compartmentalised viral reactivation. In our view, the strong correlation between CMV-specific immunity and development of hepatitis, as well as the apparent effectiveness of valganciclovir, suggests a causal role for CMV in the aetiology of αPD-1/αCTLA-4-related hepatitis.
We do not presently know whether CMV-specific CD4+ TEM cells inflict liver injury directly or provoke bystander T cell responses50. Administration of αPD-1 or αCTLA-4 has been associated with CMV reactivation in colon, so it is probable that CMV also reactivates in liver during dual therapy51. In two patients with high-grade hepatitis, we observed liver inflammation subsided immediately after starting valganciclovir. In our view, the likely presence of viral antigen and apparent responsiveness to valganciclovir is consistent with a direct pathological effect of CMV-specific T cells, although we accept this will be hard to prove in patients.
Better understanding the contribution of anti-viral T cell immunity to checkpoint blockade-related adverse reactions leads us to unexpected solutions for preventing serious complications of cancer immunotherapy. From a clinical perspective, the immunological mechanisms described illustrate how patients’ medical histories, especially prior exposure to pathogens, impact their experience of cancer and response to therapy.
Methods
Study approval and patient management
This study involving human research participants was performed in accordance with the Declaration of Helsinki and all applicable German and European laws and ethical standards. Specifically, specimens were obtained from patients with Stage III or IV melanoma participating in a single-centre observational clinical trial authorised by the Ethics Committee of the University of Regensburg (approval 16-101-0125) and registered with clinicaltrials.gov (NCT04158544). All participants gave full, informed written consent. The first reported patient was recruited in October 2016 and the last reported patient was recruited in July 2020. Patients received standard-of-care treatment according to local guidelines (Fig. 1a). Stage IV patients with unresectable metastatic disease who received first- or second-line checkpoint inhibitor therapy were initially treated with Nivolumab (αPD-1; Bristol-Myers Squibb) and Ipilimumab (αCTLA-4; Bristol-Myers Squibb) for four cycles, and thereafter with Nivolumab maintenance therapy (3 mg/kg at 3-week intervals). Those patients with complete resection of Stage III melanoma who received adjuvant first-line checkpoint inhibitor therapy were treated for up to 1 year with Pembrolizumab (αPD-1; MSD) or Nivolumab.
Clinical flow cytometry
Detailed step-by-step protocols for preparation and analysis (including specimen gating strategies) of clinical samples by flow cytometry are available through Protocol Exchange52. In brief, peripheral blood samples were collected into ethylenediaminetetraacetic acid (EDTA)-vacutainers by venepuncture and then delivered to the immune monitoring laboratory at ambient temperature. Pre-analytical samples were stored for up to 4 h at 4 °C until processing. Whole blood was stained with DuraClone reagents (Duraclone IM Phenotyping Basic Tube, B53309; Duraclone IM T cell Subsets Tube, B53328; Duraclone IM TCRs Tube, B53340; Duraclone IM Treg Tube, B53346; Duraclone IM B cells Tube, B53318; Duraclone IM Dendritic Cells Tube, B53351; all from Beckman Coulter, Krefeld, Germany). Data were recorded with a NaviosTM cytometer running Cytometry List Mode Data Acquisition and Analysis Software version 1.3 (Beckman Coulter). Blinded analyses were performed by an experienced operator using Kaluza version 2.1 according to gating strategies illustrated in Supplementary Figs. 2–8.
Detection of CMV-reactive T cells by flow cytometry
Detailed step-by-step protocols are available through Protocol Exchange53. Briefly, frozen PBMC from patients were thawed and resuspended in RPMI medium (ThermoFisher, Schwerte, Germany) supplemented with 5% heat-inactivated pooled, male-only human AB serum (ZKT Tübingen, Germany), 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mM Glutamax (ThermoFisher). Cells were plated in 96-well round-bottom plates at 1 × 106 cells in 150 µl/well then incubated at 37 °C with 5% CO2. After 6 h, cultures were stimulated with 5 µg/ml CMV Lysate (Origene) and αCD28/αCD49 for 18 h. In some conditions, cultures were treated with neutralising monoclonal antibodies against PD-1 (MAB10864, R&D) plus CTLA‐4 (MAB3254, R&D) at 5 µg/ml each or mouse IgG1 isotype control (MAB002, R&D) at a final concentration of 10 µg/ml. During the last 4 h of cell culture, protein secretion was blocked with Protein Transport Inhibitor Cocktail (ThermoFisher) containing Brefeldin A und Monensin. Cytokine production was then assessed by flow cytometry. Dead cells were excluded with ViaKrome-808 Fixable Viability Dye (Beckman Coulter). Staining was performed in Cell Staining Buffer (BioLegend) with 10% FcR Block (Miltenyi). Cells were fixed and permeabilised using the eBioscience IC Fixation Buffer and Permeabilization Buffer (eBiosciences, ThermoFisher). Data were recorded with a Cytoflex LXTM cytometer running CytoExpert Software (Beckman Coulter) and analysed using Kaluza version 2.1 (Beckman Coulter) according to the gating strategy shown in Supplementary Fig. 11.
18F-FDG PET/CT imaging
Hepatic glucose metabolism as a measure of liver inflammation34 was analysed retrospectively in all 32 patients who underwent pretreatment 18F-FDG positron emission tomography and computed tomography (PET-CT) imaging as part of routine tumour staging shortly before starting immunotherapy. After overnight fasting, whole-body PET acquisitions covering at least the trunk were started 60–90 min after i.v. injection of 18F-FDG (3 MBq per kg body weight) on a Biograph Sensation 16 LSO or Biograph mCT40 Flow PET/CT scanner (both Siemens Healthcare, Germany) and lasted 18–24 min depending on patient size. The same area was covered by a low-dose CT scan (tube current <50 mAs, tube voltage 120 kV) if no contrast agents were used. Otherwise 130 ml of AccupaqueTM 300 (GE Healthcare) was applied as intravenous contrast agent with consecutive full-dose CT acquisition (120 kV, <100 mAs). PET images (slice thickness 5 mm) were corrected for random coincidences, decay, scatter, and attenuation and reconstructed iteratively using vendor parameter presets. PET and CT images were checked for breathing artifacts and scaled to standardised uptake values (SUV). SUVmean Blood was measured in a thread-like region-of-interest (ROI) manually set into the aorta and SUVmean Liver in a spherical ROI in the right liver lobe using the program ROVER (Version v3.0.35, Helmholtz-Zentrum Dresden-Rossendorf, Germany). SUR was calculated as with correction for the distribution time T of 18F-FDG to the reference time T0 of 75 min post injection54: SUR = (T0/T) × (SUVmean liver / SUVmean blood).
Routine clinical investigations
Routine biochemical and haematological investigations were performed by an in-house accredited diagnostic laboratory (Institute of Clinical Chemistry and Laboratory Medicine, UKR). Virological investigations were conducted by an in-house accredited laboratory (Institute of Clinical Microbiology and Hygiene, UKR) following routine diagnostic procedures. CMV-reactive T cells were quantified by IFN-γ ELISPOT (Lophius, Germany) according to the manufacturer’s instructions in an accredited laboratory (UKR).
Statistics, data transformations and visualisation
Significance tests and curve-fitting were performed with GraphPad Prism 6.04 (GraphPad Software, Inc., La Jolla, USA) or SPSS® version 25 (IBM Analytics, New York, USA). As indicated, data were analysed using a two-tailed Mann–Whitney (M.W.) test, two-tailed Fisher’s exact test (F.E.), D’Agostino & Pearson’s normality test (K2), one-way or two-way ANOVA, two-tailed t-tests, log-rank survival analysis, receiver-operator characteristic (ROC) analysis or calculating pairwise Pearson correlations (R2). Where stated in the figure legends, p-values were adjusted for multiple comparison using Benjamini–Hochberg (B.H.) correction or Bonferroni correction, but otherwise no adjustment was made.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Peer Review File
Reporting Summary
Source data
Source Data
Supplementary information
The online version contains supplementary material available at 10.1038/s41467-021-21572-y.
Acknowledgements
The authors gratefully acknowledge the financial support of Bristol-Myers Squibb and the BMS Foundation (Award FA-19-009) in the form of unrestricted research grants. This study was partly supported by grants from the German Research Foundation to S.H. (DFG HA 8481/1-1) and J.A.H. (DFG HU 1838/1-1; DFG HU 1838/2-1). L.C. is a Marie Skłodowska-Curie Research Fellow affiliated with INsTRuCT and receives funding from the European Union’s Horizon 2020 research and innovation programme (Award 860003). The authors thank Dr. Michael Kapinsky of Beckman Coulter GmbH for advice and support with clinical flow cytometry. The authors also thank Prof. Tobias Pukrop and staff of the Interdisciplinary Center for drug Tumor Therapy (ICT) for supporting collection of clinical samples. This work would not have been possible without the outstanding technical support of Erika Ostermeier, Marina Sorokina, Veronika Menath, Anke Hofmann and Joachim Schweimer.
Author contributions
J.A.H. designed the immune monitoring studies and other experiments, analysed the results and wrote the manuscript; K.K. organised and performed immune monitoring studies; P.R. designed and performed the experiments; J.J.W., J.K. and B.S. performed the virological analyses; K.E. provided expert histopathological descriptions; M.S., L.B. and D.H. performed the radiological and molecular imaging analyses; G.G., F.Z. and R.S. provided expert statistical and bioinformatics advice; L.C. quality-checked the manuscript; C.B. and R.B. were responsible for the routine clinical laboratory analyses; M.M. and K.D. provided the biological samples; H.L.S. and F.B. performed the experiments; H.J.S. provided infrastructural support; E.K.G., J.M.W. and S.H. provided material support, patient samples and critical feedback throughout the project. All authors approved the final version of the manuscript.
Data availability
Data supporting the findings of this study are available within the article and its Supplementary information files, or are available from the corresponding author subject to legal restrictions governing use of personal information. Source data are provided with this paper.
Competing interests
S.H. declares he has received consulting fees and speaker’s honoraria from BMS and Merck Sharp & Dohme (MSD). All other authors declare no competing interests.
Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BINIMETINIB, ENCORAFENIB, IPILIMUMAB, NIVOLUMAB, PREDNISOLONE | DrugsGivenReaction | CC BY | 33664251 | 19,603,137 | 2021-03-04 |
What was the dosage of drug 'PREDNISOLONE'? | Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis.
Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.
Introduction
Treatment with anti-programmed cell death protein-1 (αPD-1) alone or combined with anti-cytotoxic T-lymphocyte-associated protein 4 (αCTLA-4) has greatly improved the prognosis of metastatic melanoma with a substantial fraction of patients achieving long-lasting partial or complete clinical responses1–6. The principal limitation of αPD-1/αCTLA-4 dual therapy is the relatively high rate of immune-related complications, which commonly include colitis, hepatitis and thyroiditis, but may also include pneumonitis, myocarditis and encephalitis7,8. Such adverse events range from mild reactions to life-threatening presentations, but are nevertheless clinically significant incidents that influence patient management9,10. Avoidance of complications has led to a somewhat complicated treatment decision-making process (Fig. 1a) that seeks to balance individual risk and capacity to tolerate adverse reactions against the superior clinical responses achieved with dual αPD-1/αCTLA-4 therapy over αPD-1 monotherapy11–13.Fig. 1 Individual predisposition to hepatitis after αPD-1/αCTLA-4 treatment.
a Individualised treatment of melanoma is guided by tumour staging, presence of B-RAF mutations and fitness-for-toxicity. b Colitis, hepatitis and thyroiditis are common immune-related complications of dual therapy with Nivolumab plus Ipilimumab; 31.4% of patients experienced two or more of these immune-related adverse reactions (n = 89). c Colitis, hepatitis and thyroiditis occurred independently and were not significantly associated with clinical response (n = 89; F.E). d–h Patients who developed hepatitis of any grade following dual therapy lacked biochemical signs of liver inflammation before treatment. In particular, no clinically meaningful differences in plasma levels of d aspartate transaminase (AST; n = 87; M.W.; Bonferroni-corrected p-value, m = 5), e alanine transaminase (ALT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), f gamma glutamyl transaminase (γ-GT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), g total bilirubin (n = 87; M.W.; Bonferroni-corrected p-value, m = 5), or h C-reactive protein (CRP; n = 85; M.W.; Bonferroni-corrected p-value, m = 5) were observed between patients who developed hepatitis and those who did not. Median values are indicated by a red line. i, j Biochemical markers of tumour burden were not different between patients who developed hepatitis and those who did not. i Pre-treatment levels of lactate dehydrogenase (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. j Pre-treatment levels of protein S100 (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). k–m No association was observed between seropositivity for k hepatitis B virus core antigen (HBcAg; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), l hepatitis C virus (HCV; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), or m hepatitis E virus (HEV; n = 67; F.E.; Bonferroni-corrected p-value, m = 3) and development of hepatitis following dual therapy. n No association was observed between rounds of αPD-1/αCTLA-4 administered and development of hepatitis (n = 89; M.W.).
Our aetiological understanding of colitis, hepatitis and thyroiditis caused by immune checkpoint blockade remains incomplete14; however, these treatment-related conditions are clearly different from known autoimmune diseases15,16. Such adverse reactions are usually attributed to generalised dysregulation of T cells17,18 or autoantibodies15. Here, we explore a different view—namely, that individual patients are predisposed to particular treatment-related complications by virtue of pathogen-specific memory T cells present in their repertoire before immune checkpoint blockade is given.
Cytomegalovirus (CMV) seroprevalance amongst European adults is over 50%. Primary CMV infection usually presents during young adulthood as an acute febrile illness, after which life-long latency is established. The exact sites and mechanisms of CMV latency are not fully resolved, but myelomonocytic cells in blood and tissues are major reservoirs19. CMV reactivation characteristically follows immune compromise caused by immunosuppressive therapy or other viral infections20. Clinical manifestations of CMV reactivation are variable, ranging from classic febrile illness to tissue-invasive disease presenting as colitis, hepatitis, pneumonitis or encephalitis21. Reactivation of CMV causes cellular injury through the cytopathic effect of viral replication, but more conspicuously through triggering T cell immunity. Pneumonitis in transplant recipients illustrates how CMV-reactive T cells provoke extensive, life-threatening inflammation despite low-level viral replication22. Even in anatomical locations from which T cells are normally excluded, such as the retina, T cell-mediated responses significantly contribute to CMV-related disease. Thus, low-level and compartmentalised reactivation of CMV can be responsible for serious acute immunopathology in humans23–25.
Cycles of CMV latency and reactivation lead to a now well-recognised phenomenon of memory inflation, which is typified by failure of primed CMV-specific CD8+ T cell populations to contract and give rise to central memory T cells26. Instead, a dominant pool of effector memory CD8+ T cells that does not become functionally exhausted is maintained27. Such inflationary CD8+ T cells achieve high frequencies over time, sustained through repetitive stimulation by viral reactivation or long-term persistence of viral antigens28. Memory inflation is described as an exclusive feature of CD8+ effector T cell responses, although durable expansion of CMV-specific CD4+ T cells can occur in transplant recipients29.
This study identifies pre-therapy expansion of CD4+ effector memory T cells (TEM) in CMV-infected patients with metastatic melanoma as a prognostic marker of αPD-1/αCTLA-4-related hepatitis. Opting for αPD-1 monotherapy or prophylactic valganciclovir in CMV IgG+ patients with unresectable metastatic disease and pre-treatment expansion of CD4+ TEM cells reduces their risk of hepatitis. We conclude that sub-clinical reactivation of CMV plays a previously unsuspected role in the immunopathogenesis of αPD-1/αCTLA-4-related hepatitis in a subgroup of patients.
Results
Clinical features do not predict αPD-1/αCTLA-4-related hepatitis
If immune-related complications of αPD-1/αCTLA-4 therapy resulted solely from treatment-induced immunological effects30,31, we might expect hepatitis, colitis and thyroiditis to coincide often32 (Fig. 1b). However, no such associations were found in a cohort of 89 patients with metastatic melanoma treated with αPD-1/αCTLA-4 dual therapy (Fig. 1c, Supplementary Fig. 1 and Supplementary Tables 1–3). This raises the possibility that some individuals are predisposed to particular adverse reactions.
In this study, we focused on factors that predispose to αPD-1/αCTLA-4-related hepatitis. Except for patients who developed hepatitis being generally younger (Supplementary Table 4) no associations were found between incidence of hepatitis and pre-treatment clinical variables (Supplementary Tables 4 and 5). Conventional biochemical markers of liver dysfunction, systemic inflammation or tumour burden did not discriminate between patients who did or did not develop hepatitis (Fig. 1d–j). We found no associations between incidence of hepatitis and seropositivity for hepatitis B virus (HBV), hepatitis C virus (HCV) or hepatitis E virus (HEV; Fig. 1k–m). Incidence of hepatitis was not greater with more rounds of αPD-1/αCTLA-4 therapy; in fact, as immune-related complications are reason to withhold treatment, patients who developed hepatitis tended to receive fewer rounds of αPD-1/αCTLA-4 (Fig. 1n). Autoimmune hepatitis-related autoantibodies were not associated with risk of hepatitis (Supplementary Table 6). In short, case history and routine clinical investigations did not predict hepatitis after dual therapy in our study cohort.
CD4+ TEM cell expansion predicts αPD-1/αCTLA-4-related hepatitis
We next profiled circulating leucocyte subsets immediately prior to start of dual therapy in a training set of n = 44 patients with unresectable metastatic melanoma (Supplementary Figs. 2–8). Comparing the frequency of 50 principal leucocyte subsets between patients who subsequently did (n = 18) or did not (n = 26) develop hepatitis revealed significant over-representation of CD4+ TEM cells associated with hepatitis (Fig. 2a, b). This observation was confirmed in a validation set (n = 45) of similar patients (Fig. 2c). Baseline expansion of CD4+ TEM cells was a fair discriminator (AUROC = 0.706) of patients who did or did not later develop hepatitis in the validation set (Fig. 2d). Strikingly, CD4+ TEM cell frequencies in all patients with completely resected disease were normally distributed with no extreme cases of baseline CD4+ TEM cell expansion, allowing us to set a threshold below which 99% of patients should fall (Fig. 2e). Applying this stringent cut-off to our validation cohort of patients with unresectable metastatic disease (Fig. 2f) allowed us to correctly predict hepatitis in 6 of 6 patients with CD4+ TEM≥21% (specificity = 100%) and correctly identify 6 of 20 patients who developed hepatitis (sensitivity = 30.0%). CD4+ TEM≥21% patients were not predisposed to colitis (Fig. 2g), thyroiditis or superior clinical responses to therapy (Supplementary Table 7). Hepatitis was not more severe in CD4+ TEM≥21% patients compared to CD4+ TEM<21% patients (Fig. 2h) and no difference in time-to-first presentation was observed (Fig. 2i). Hence, baseline CD4+ TEM expansion is a specific, but relatively insensitive prognostic marker of individuals who are predisposed to hepatitis after αPD-1/αCTLA-4 therapy. Owing to its low sensitivity, classifying patients as CD4+ TEM<21% has limited clinical utility; however, specifically identifying cases at high-risk of hepatitis before treatment is useful from a research perspective because we can then prospectively study the immunological basis of their predisposition.Fig. 2 Circulating CD4+ T effector memory cell frequency predicts hepatitis after Nivolumab plus Ipilimumab treatment.
a Peripheral blood samples were collected from melanoma patients with metastatic disease receiving αPD-1/αCTLA-4 therapy immediately before administration of the first dose (n = 89). Leucocyte subsets differentially represented in patients with or without hepatitis were identified in a randomly assigned training set (B.H.-corrected t-tests; n = 44; m = 50; FDR = 0.25). Red dots indicate significantly differently represented subsets. Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. b CD4+ TEM % in training set patients with or without treatment-related hepatitis (n = 44; M.W.). Median values are indicated by a red line. c CD4+ TEM % in validation set patients with or without treatment-related hepatitis (n = 45; M.W.). d ROC analysis of CD4+ TEM % as a discriminatory marker for treatment-related hepatitis in the validation set (n = 45). e Comparison of the bimodal distribution of CD4+ TEM % in patients with unresectable metastatic disease (n = 107) and the normal distribution (n = 49; K2 = 2.79; p = 0.248) of CD4+ TEM % in patients with completely resected tumours. A cut-off of CD4+ TEM ≥ 21% was set (indicated by a dashed red line) below which 99% of completely resected tumour cases should fall. Four pink points represent CD4+ TEM≥21% patients with metastatic disease who were electively treated with αPD-1 monotherapy. f In the validation set, 68.9% patients were correctly classified using a cut-off of CD4+ TEM ≥ 21 %, whereas 55.6% were correctly classified under the no-information model (n = 45; F.E.). g CD4+ TEM ≥ 21 % is not a marker of predisposition to αPD-1/αCTLA-4-related colitis (n = 89; F.E.). h CD4+ TEM≥21% patients did not experience more severe hepatitis than CD4+ TEM<21% patients (n = 38; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. i Time-to-first presentation of hepatitis was not different between CD4+ TEM≥21% (n = 12) and TEM<21% (n = 26) patients (log-rank). j Twelve of 12 patients with unresectable metastatic melanoma and CD4+ TEM ≥ 21% developed hepatitis after αPD-1/αCTLA-4 dual therapy. By contrast, 3 of 4 CD4+ TEM≥21% patients treated with αPD-1 monotherapy did not develop hepatitis (F.E.; p = 0.007).
Opting for αPD-1 monotherapy reduces risk of hepatitis
Although αPD-1 monotherapy achieves fewer sustained clinical responses in patients with metastatic melanoma, it causes fewer adverse reactions than αPD-1/αCTLA-4 dual therapy1. Therefore, there is a clear rationale for avoiding αPD-1/αCTLA-4 dual therapy in patients at risk of hepatitis. Four CD4+ TEM≥21% patients with metastasic disease presented during our study, but were electively treated with αPD-1 monotherapy (Fig. 2j). Whereas 12 of 12 CD4+ TEM≥21% patients treated with αPD-1/αCTLA-4 dual therapy developed hepatitis, 3 of 4 CD4+ TEM≥21% patients who received αPD-1 monotherapy remained hepatitis free. Reducing the incidence hepatitis by opting for αPD-1 monotherapy hints that CTLA-4 blockade may be mechanistically important for development of hepatitis in CD4+ TEM≥21% patients33.
CD4+ TEM frequency is an independent predictor of hepatitis
We next investigated possible causes of baseline CD4+ TEM expansion. To establish CD4+ TEM expansion as an independent risk factor, we first sought to exclude possible confounding covariables. Baseline CD4+ TEM≥21% was not related to sex, age or body-mass index (Supplementary Table 7 and Fig. 3a, b). No significant correlation was observed between baseline CD4+ TEM % and serum levels of C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT) or total bilirubin (Fig. 3c–g). Because glucose metabolism provides a reliable measure of liver inflammation34, we were able to further rule out liver inflammation prior to therapy as a predisposing cause of CD4+ TEM≥21% hepatitis by estimating hepatic glucose uptake in patients who underwent 18F-fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT studies as part of routine tumour staging shortly before starting immunotherapy (Fig. 3h). This retrospective comparison showed 18F-FDG standard uptake ratios (SURmean liver) were higher in CD4+ TEM<21% patients than CD4+ TEM≥21% patients with hepatitis (Fig. 3i). Therefore, our biochemical and radiological investigations argue against pre-treatment liver inflammation as a common cause for baseline CD4+ TEM expansion and treatment-related hepatitis.Fig. 3 CD4+ TEM frequency is an independent predictor of αPD-1/αCTLA-4-related hepatitis.
a CD4+ TEM % did not correlate with age (n = 89; Pearson). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM % did not correlate with body mass index (n = 89; Pearson). c CD4+ TEM % did not correlate with C-reactive protein (CRP) levels (n = 85; Pearson). d CD4+ TEM % did not correlate with aspartate aminotransferase (AST) levels (n = 87; Pearson). e CD4+ TEM % did not correlate with alanine aminotransferase (AST) levels (n = 89; Pearson). f CD4+ TEM % did not correlate with gamma-glutamyltransferase (γ-GT) levels (n = 89; Pearson). g CD4+ TEM % did not correlate with total bilirubin levels (n = 89; Pearson). h Glucose metabolism measured by 18F-fluoro-2-deoxy-d-glucose (18F-FDG) uptake in PET/CT studies is a quantitative marker of liver inflammation. Calculating standard uptake ratio (SURmean Liver) allows accurate quantification of 18F-FDG uptake in liver by correcting for differential clearance of tracer from blood and liver parenchyma. Higher SURmean Liver values indicate more severe inflammation. T0 = reference time point at 75 min post-injection and T = actual scan time. i SURmean Liver was lower in CD4+ TEM≥21% patients than CD4+ TEM<21% patients who developed hepatitis indicating less inflammation at baseline in the CD4+ TEM≥21% subgroup (n = 28; Pearson). j CD4+ TEM≥21% was not associated with the number of organs containing one or more metastases ≥1.5 cm in diameter (n = 103; F.E.). k CD4+ TEM≥21% was not associated with the presence of hepatic metastases (n = 103; F.E.). l CD4+ TEM % did not correlate with lactate dehydrogenase (LDH) levels (n = 88; Pearson). m CD4+ TEM % did not correlate with protein S100 levels (n = 88; Pearson). n CD4+ TEM≥21% was not associated with any prior therapy (n = 89; F.E.).
Because CD4+ TEM expansion is principally a feature of metastatic melanoma (Fig. 2e), we next asked whether CD4+ TEM% was somehow associated with tumour burden. No relationship was found between CD4+ TEM% and the number of organs containing metastases, presence of hepatic metastases or serum lactate dehydrogenase (LDH) and protein-S100 serum levels (Fig. 3j–m and Supplementary Table 7). There was a tendency for CD4+ TEM≥21% patients to have received previous therapy of any type (including BRAFi/MEKi or Talimogen laherparepvec) but besides implying a longer disease course before starting dual therapy, we see no mechanistic interpretation because these drugs share no common pharmacological action (Fig. 3n). In short, we found no obvious clinical association to explain the predisposition of CD4+ TEM≥21% patients to hepatitis.
CD4+ TEM cell expansion is associated with chronic T cell activation
Although CD4+ T cell counts were not different between CD4+ TEM<21% and CD4+ TEM≥21% patients (Supplementary Table 7), there were significantly fewer circulating naïve T cells in CD4+ TEM≥21% patients (Fig. 4a). This reduction was complemented by increased absolute numbers of CD4+ TEM and TEMRA cells (Fig. 4b, c) whereas central memory T cell (TCM) counts tended to be lower in CD4+ TEM≥21% patients (Fig. 4d). We next defined other leucocyte subsets that correlated with CD4+ TEM % in both our training and validation cohorts (Fig. 4e). Most covariant populations were T cells, particularly CD4+ T cell subsets. Changes in the CD4+ T cell compartment of TEM≥21% patients were consistent with chronic activation, particularly downregulation of CD27 and upregulation of CD57, HLA-DR and CD279 expression (Fig. 4f–i). Similar differences were detected in CD8+ T cells (Supplementary Fig. 9). Notably, CD4+ TEM≥21% patients tended to have higher frequencies of CD160+ CD244+ exhausted CD8+ T cells than CD4+ TEM<21% patients (Fig. 4j).Fig. 4 CD4+ TEM cell enrichment is associated with chronic activation and increased numbers of effector memory CD4+ T cells.
a–d Increased CD4+ TEM frequency before treatment reflects a decrease in circulating naïve CD4+ T cells and an increase in circulating numbers of CD4+ TEM cells. a Baseline naïve CD4+ T cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 5.2 ⨯ 10−5). b Baseline CD4+ TEM cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 8.0 ⨯ 10−4). c Baseline CD4+ TEMRA cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). d Baseline CD4+ TCM cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. e Pairwise correlations between CD4+ TEM cell frequency and other leucocyte subset frequencies in the training and validation sets (n = 103; Pearson). Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. f Baseline CD27+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.2 ⨯ 10−10). g Baseline CD57+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 2.0 ⨯ 10−9). h Baseline HLA-DR+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.1 ⨯ 10−5). i Baseline CD279+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). j Baseline CD160+ CD244+ CD8+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). k Baseline Torque Teno Virus (TTV) loads. Uninfected patients were censored from analysis (n = 74; M.W.; Bonferroni-corrected p-value, m = 60). Median values are indicated by a red line.
Most adults are persistently infected with Torque Teno Virus (TTV), a non-enveloped, circular, single-stranded DNA virus of the Anellovirus family that causes no apparent disease. T cell immunity controls TTV replication in healthy people, whereas TTV copy number in immunocompromised individuals is increased; therefore, TTV load in plasma is a useful marker of immune competence. Despite accumulating chronically activated and exhausted T cells, TTV load in CD4+ TEM≥21% versus CD4+ TEM<21% patients was not different, implying that CD4+ TEM≥21% patients are not generally immunocompromised (Fig. 4k).
CD4+ TEM cell expansion correlates with immunity to CMV
To briefly summarise, baseline expansion of CD4+ TEM cells identifies a subset of patients with metastasic melanoma who are predisposed to αPD-1/αCTLA-4-related hepatitis. These patients show signs of persistent or recurrent CD4+ and CD8+ T cell responses35, but are otherwise clinically and immunologically unremarkable. It is usually very difficult to isolate factors responsible for such a non-specific immunological picture36. Fortunately, a surprising pattern emerged from our dataset: CD4+ TEM≥21% patients mostly presented between September and February (Fig. 5a). This seasonal influence was apparent over all 4 years of the study, leading us to think that CD4+ TEM expansion might be driven by a pathogen. Active infections with hepatitis viruses, including HBV and HCV, are relative contraindications to αPD-1/αCTLA-4 therapy (Supplementary Table 7), so we were forced to consider possible involvement of other hepatotropic viruses, such as HEV and herpesgroup viruses.Fig. 5 CD4+ TEM cell expansion correlates with immunity to cytomegalovirus.
a Seasonal presentation of CD4+ TEM≥21% patients between 2017 and 2020 (n = 103; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM≥21% status was associated with high serum levels of anti-CMV IgG antibodies (n = 100; F.E.; p = 1.2 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. c CD4+ TEM≥21% status was associated with CMV-reactivity in pp65 ELISPOT (n = 53; F.E.; p = 9.0 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. d Development of hepatitis was associated with CMV-seropositivity and CD4+ TEM≥21% status (n = 89). Median values are indicated by a red line. e ROC analysis showing CD4+ TEM % is a superior discriminator of patients at risk of hepatitis when considering only CMV IgG+ cases as opposed to all cases. f Classification of patients with unresectable metastatic melanoma who did or did not develop αPD-1/αCTLA-4-related hepatitis according to CMV IgG status and baseline CD4+ TEM cell frequency using a revised cut-off of CD4+ TEM ≥ 16%. Red boxes indicate 34 of 40 (85%) cases correctly classified by our model (n = 40; F.E.; p = 1.4 ⨯ 10−5). Green box indicates 2 of 17 (11.7%) cases predicted to develop hepatitis who did not. Pink box indicates 4 of 23 (17.4%) cases predicted not to develop hepatitis who did. Blue box indicates 19 of 49 CMV IgG− patients not considered by our model who developed hepatitis.
Latent CMV infection is prevalent amongst European adults and involves many organs, including liver. Compartmentalised reactivation of CMV infection occurs in immunocompromised individuals and those with concomitant viral upper respiratory tract infections20. In our patients, we found a strong association between serum CMV-specific IgG antibody levels and CD4+ TEM status (Fig. 5b). Furthermore, T cell reactivity against CMV pp65 peptides in an IFN-γ enzyme-linked immunospot (ELISPOT) assay was tightly associated with CD4+ TEM status (Fig. 5c). These results led us to hypothesise a causal relationship between compartmentalised, sub-clinical CMV reactivation in liver and chronic enrichment of CD4+ TEM cells in blood.
Because baseline CD4+ TEM cell expansion was mainly a feature of CMV IgG+ patients (Fig. 5d), we next asked whether incorporating CMV IgG status could improve our predictive model. When considering only CMV IgG+ cases, CD4+ TEM % was a more discriminatory marker of hepatitis (Fig. 5e). Therefore, using our training set filtered for CMV IgG+ cases, we revised our cut-off to CD4+ TEM ≥ 16% in CMV IgG+ cases in order to achieve a better compromise between specificity and sensitivity (Supplementary Fig. 10). The new cut-off performed well in the validation set with a correct classification rate of 81.0% (positive predictive value (PPV) = 85.7% and negative predictive value (NPV) = 78.6%) compared to 42.9% under the no-information model.
For descriptive purposes, we can consider the distribution of patients from the combined training and validation sets according to CMV IgG and CD4+ TEM status (Fig. 5f). Our predictive model explains the occurrence of hepatitis in 34 of 89 (38.2%) of all patients (red boxes). Two of 17 (12%) CMV IgG+ CD4+ TEM≥16% patients (green box) did not develop hepatitis: one of these received four rounds of αPD-1/αCTLA-4 therapy and registered no complications; however, the other received only 1 round of αPD-1/αCTLA-4 before treatment with prednisolone from weeks 2 to 7 for colitis. We speculate 4 of 23 CMV IgG+ CD4+ TEM<16% patients who were incorrectly predicted as hepatitis-negative (pink box) were sampled at an early stage of CD4+ TEM cell expansion and our test was not sensitive enough to discriminate the change. Our model does not explain why 19 of 49 CMV IgG− patients developed hepatitis (blue box) but we believe these represent an aetiologically distinct subset.
CMV-reactive CD4+ T cells are enriched in CD4+ TEMhigh patients
We next asked whether CMV-reactive CD4+ T cells were enriched in patients with baseline CD4+ TEM expansion. Peripheral blood mononuclear cells (PBMC) were stimulated in culture for 18 h with CMV lysates before IFN-γ, TNFα, IL-17, IL-4 and CD69 expression was measured by flow cytometry (Fig. 6a and Supplementary Figs. 11 and 12). To detect hyporesponsive CMV-specific T cells, paired cultures were also stimulated in the presence of neutralising antibodies against PD-1 and CTLA-4. In contrast to CMV IgG− and CMV IgG+ CD4+ TEM<16% patients, we readily detected IFN-γ-producing, CMV-reactive CD4+ T cells in CMV IgG+ CD4+ TEM≥16% patients (Fig. 6b). This difference implies a higher number of circulating IFN-γ-producing, CMV-reactive CD4+ T cells (Fig. 6c). Proportions of CMV-reactive CD4+ T cells expressing IL-17, IL-4 or only TNFα were too low to quantify accurately.Fig. 6 CMV-reactive CD4+ T cells are enriched in patients with CD4+ TEM cell expansion.
CMV-reactive CD4+ T cells in patients with unresectable metastatic melanoma were assayed by in vitro stimulation with CMV lysates (blue boxes). Neutralising antibodies (red hatching) were used to detect T cells unable to respond to CMV antigens owing to expression of PD-1 or CTLA-4. T cell responses were quantified by flow cytometry analysis of cytokine expression. a Example data from a CMV IgG+ CD4+ TEM≥16% patient who developed hepatitis. Gating of live, singlet, IFN-γ-producing CD4+ T cells is illustrated in Supplementary Fig. 11. b Frequencies of IFN-γ-producing CD4+ T cells in patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers. c Absolute numbers of circulating IFN-γ-producing CD4+ T cells patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers.
Valganciclovir reverses αPD-1/αCTLA-4-related hepatitis
Strong associations between T cell immunity against CMV, expansion of CD4+ TEM and risk of treatment-related hepatitis imply an underlying pathogenic mechanism; however, to demonstrate a causal relationship, we needed to establish that inhibiting CMV replication was effective in treating or preventing hepatitis. Valganciclovir is an anti-viral agent licensed for therapy and prophylaxis of CMV infections in immunocompromised patients. It is a widely used and safe drug with a well-known and broadly acceptable profile of adverse effects. Therefore, we next gave valganciclovir treatment to two patients with αPD-1/αCTLA-4-related hepatitis.
The first patient was a comparatively fit 54-year-old man with a new diagnosis of metastatic melanoma (Fig. 7a). Staging CT revealed multiple lung and bone metastases, but no metastasis to liver or lymph nodes. At baseline, the patient was CMV-IgG+ and CD4+ TEM = 18.7% (Fig. 7b). Nivolumab plus Ipilimumab were given at 0, 3 and 6 weeks. A fourth round of αPD-1/αCTLA-4 at week 9 was omitted owing to joint pain and the patient received two rounds of Denosumab (αRANKL). Nivolumab monotherapy was administered in weeks 12, 16, 20 and 24. Staging CT at week 14 showed a partial clinical response with significant regression of pulmonary metastases; hence, checkpoint blockade was of clear clinical benefit.Fig. 7 Case 1: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 54-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction, withdrawal and re-introduction of valganciclovir treatment. c The patient presented at the end of week 40 with recrudescent hepatitis and was treated with 900 mg/day valganciclovir for 2 days prior to liver biopsy. Histopathological image of the liver biopsy (H&E staining; scale bar 500 µm). d Generally, the liver parenchyma appeared normal (H&E staining; scale bar 100 µm). e Only a few lymphocytes and sparse necrotic hepatocytes were observed in portal areas with small bile plugs (arrows) with no signs of hepatitis (H&E staining; scale bar 100 µm).
The patient received a dose of αPD-1 monotherapy in week 32. Four weeks later, he presented in clinic with grade 4 hepatitis. Strong reactions against pp65 and IE-1 peptides were measured by ELISPOT. Accordingly, the patient was treated with 900 mg/day valganciclovir plus prednisolone. Liver function tests (LFTs) returned to normal, so over the subsequent 2 weeks, prednisolone was weaned and then valganciclovir was withdrawn. Seven days later, the patient returned to clinic with deranged LFTs. Valganciclovir and prednisolone were both reinstated, leading to a rapid normalisation of LFTs. Two days later, a for-cause liver biopsy was performed (Fig. 7c–e). The tissue was essentially normal, although a few dying hepatocytes and isolated lymphocytes were observed in the portal areas. Immunohistochemical staining for CMV and nested CMV PCR from fixed biopsy material were negative. The patient remained clinically stable for 9 days, so he was again weaned from prednisolone by the start of week 43; however, on this occasion, 900 mg/day valganciclovir treatment was continued. After complete withdrawal of prednisolone, while still receiving valganciclovir, the patient’s LFTs remained stable for a further 4 weeks. At the start of week 47, valganciclovir was withdrawn for a second time. Subsequently, the patient did not develop hepatitis and required no further steroids. The patient received further doses of αPD-1 monotherapy in weeks 54 and 58 without signs of recurrent liver injury. To us, this suggests the T cell antigens driving hepatitis in this patient were absent after valganciclovir treatment. In our clinical opinion, despite the absence of detectable virus, the patient’s fast recovery and unusual relapse of hepatitis are best explained by introduction, withdrawal and reintroduction of valganciclovir.
The second patient was a 49-year-old man who had an uncomplicated first year after αPD-1/αCTLA-4 and had been receiving Encorafenib/Binimetinib therapy for 7 weeks when he developed hepatitis in week 67 (Fig. 8a, b). Hepatitis failed to resolve despite withdrawal of B-RAFi/MEKi and escalating doses of prednisolone. 900 mg/day valganciclovir was introduced at the start of week 72 and a for-cause biopsy was performed on the same day (Fig. 8b). Four days later, the patient started a course of 1 mg/day mycophenolate mofetil. Strikingly, AST, ALT and γ-GT levels declined consistently from the day after valganciclovir was given, although total bilirubin continued to rise. Starting valganciclovir treatment appeared to be temporally related to increased reactivity in CMV IE-1 ELISPOT and a small decline in CD4+ TEM frequency.Fig. 8 Case 2: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 49-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction of valganciclovir treatment. c Histopathological image of a liver biopsy taken at the start of week 72 showing signs consistent with drug toxicity, autoimmunity or viral infection (H&E staining; scale bar 500 µm). d Extensive centrilobular necrosis (arrows) involving 30–40% of hepatocytes was observed (H&E staining; scale bar 100 µm). e Dense inflammatory infiltration of lymphocytes, eosinophils and neutrophils was seen in portal areas (H&E staining; scale bar 100 µm).
Liver biopsy revealed dense infiltration by lymphocytes, eosinophils and neutrophils with an accompanying ductal reaction (Fig. 8c–e). Extensive centrilobular hepatocyte necrosis was observed, which was also associated with inflammatory infiltration. These histopathological signs of significant liver damage could have been consistent with autoimmunity or viral infection. Both histological staining for CMV and CMV PCR from fixed biopsy material were negative. Although we were unable to detect virus, it is our clinical impression that markers of liver damage responded to valganciclovir treatment.
Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis
We next asked whether valganciclovir prophylaxis could prevent αPD-1/αCTLA-4-related hepatitis in predisposed individuals. The 50th, 75th and 90th percentiles of time-to-hepatitis in CMV-IgG+ patients were 24, 52 and 84 days, respectively; therefore, we treated four CMV IgG+ CD4+ TEM≥16% patients receiving αPD-1/αCTLA-4 therapy with prophylactic valganciclovir for between 4 and 23 weeks (Fig. 9a). Two of these patients registered mild, transient transaminitis that resolved without treatment, so were not diagnosed with hepatitis. Hence, we observed no hepatitis in the four valganciclovir-treated patients, whereas 15 of 17 (88.2%) CMV IgG+ CD4+ TEM≥16% patients treated with αPD-1/αCTLA-4 and no valganciclovir prophylaxis developed clinical hepatitis (Fig. 9b). To us, these four cases are consistent with the idea that CMV plays an important aetiological role in development of hepatitis after αPD-1/αCTLA-4 therapy in a specific subset of patients.Fig. 9 Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis.
a Heatmaps showing peak values of AST, ALT and bilirubin expressed as multiples of sex-adjusted upper limit of normal ranges. Fifteen of 17 (88.2%) patients classified as CMV IgG+ CD4+ TEM≥16% at baseline subsequently developed hepatitis. In contrast, 4 of 4 CMV IgG+ CD4+ TEM≥16% patients treated with 900 mg/day prophylactic valganciclovir remained hepatitis free. b In four initial cases, prophylactic valganciclovir prevented development of hepatitis (n = 21; F.E.).
Discussion
Our study seeks to explain why a subset of patients with advanced melanoma is predisposed to hepatitis following immune checkpoint blockade. In our model, metastatic disease promotes compartmentalised CMV reactivation in latently infected individuals, possibly triggered by an unknown winter virus infection; in turn, CMV stimulates expansion of CD4+ TEM cells prior to immunotherapy. When αPD-1/αCTLA-4 therapy is given, these TEM cells might inflict liver injury directly or promote bystander T cell responses. We propose CMV-driven T cell responses are a single, but salient example of a general mechanism responsible for hepatitis after checkpoint blockade because other viruses or toxic agents could also drive chronic CD4+ T cell activation before therapy. We speculate anti-viral immunity might also explain predisposition to other adverse reactions following αPD-1/αCTLA-4 therapy, such as colitis or pneumonitis37. The remarkable overlap between organs affected by tissue-invasive CMV disease and those susceptible to immune-related adverse reactions has not escaped our attention38,39.
Being able to identify patients predisposed to hepatitis opens various possibilities for avoiding or preventing treatment-related hepatitis40. Three of four CD4+ TEM≥21% patients assigned to αPD-1 monotherapy instead of αPD-1/αCTLA-4-treatment did not develop hepatitis as predicted; therefore, baseline CD4+ TEM expansion could be taken as a relative contraindication to dual therapy. However, a more promising strategy is to suppress occult CMV reactivation. In our study, valganciclovir prophylaxis apparently prevented hepatitis in four of four CMV IgG+ CD4+ TEM≥16% patients. This approach must be refined in terms of dosing and duration of anti-viral therapy in randomised, controlled clinical trials, but could potentially achieve the superior outcomes of αPD-1/αCTLA-4 dual therapy over αPD-1 monotherapy with fewer complications.
Because baseline CD4+ TEM expansion was observed in patients with metastatic disease, but not in patients with fully resected melanoma, it is possible that disseminated melanoma promotes low-level CMV reactivation, perhaps through compromised T cell immunity, which then stimulates virus-specific CD4+ T cell expansion. The prominent association between CD4+ TEM expansion and CMV (in contrast to other herpesgroup virus infections) might simply reflect differences in tissue tropism and, we speculate, the capacity of compartmentalised CMV reactivation in liver to drive especially strong T cell responses. Seasonal variation in the incidence of CD4+ TEMhigh cases suggests that environmental factors influence expansion and contraction of the CD4+ TEM cell pool41,42. In particular, we suspect common winter viruses somehow promote CMV reactivation in liver.
Chronic, low-level exposure to viral antigens preferentially expands TEM over TCM43–49, so CMV-reactive CD4+ T cell expansion might be sustained by very little CMV replication. On-going T cell reactions against CMV in CD4+ TEMhigh patients are likely to suppress CMV replication almost completely. Our inability to detect CMV in baseline serum samples from CD4+ TEMhigh patients or liver biopsies from patients with high-grade hepatitis is a challenge for our theory; however, it may simply be beyond our technical capability to detect very low levels of compartmentalised viral reactivation. In our view, the strong correlation between CMV-specific immunity and development of hepatitis, as well as the apparent effectiveness of valganciclovir, suggests a causal role for CMV in the aetiology of αPD-1/αCTLA-4-related hepatitis.
We do not presently know whether CMV-specific CD4+ TEM cells inflict liver injury directly or provoke bystander T cell responses50. Administration of αPD-1 or αCTLA-4 has been associated with CMV reactivation in colon, so it is probable that CMV also reactivates in liver during dual therapy51. In two patients with high-grade hepatitis, we observed liver inflammation subsided immediately after starting valganciclovir. In our view, the likely presence of viral antigen and apparent responsiveness to valganciclovir is consistent with a direct pathological effect of CMV-specific T cells, although we accept this will be hard to prove in patients.
Better understanding the contribution of anti-viral T cell immunity to checkpoint blockade-related adverse reactions leads us to unexpected solutions for preventing serious complications of cancer immunotherapy. From a clinical perspective, the immunological mechanisms described illustrate how patients’ medical histories, especially prior exposure to pathogens, impact their experience of cancer and response to therapy.
Methods
Study approval and patient management
This study involving human research participants was performed in accordance with the Declaration of Helsinki and all applicable German and European laws and ethical standards. Specifically, specimens were obtained from patients with Stage III or IV melanoma participating in a single-centre observational clinical trial authorised by the Ethics Committee of the University of Regensburg (approval 16-101-0125) and registered with clinicaltrials.gov (NCT04158544). All participants gave full, informed written consent. The first reported patient was recruited in October 2016 and the last reported patient was recruited in July 2020. Patients received standard-of-care treatment according to local guidelines (Fig. 1a). Stage IV patients with unresectable metastatic disease who received first- or second-line checkpoint inhibitor therapy were initially treated with Nivolumab (αPD-1; Bristol-Myers Squibb) and Ipilimumab (αCTLA-4; Bristol-Myers Squibb) for four cycles, and thereafter with Nivolumab maintenance therapy (3 mg/kg at 3-week intervals). Those patients with complete resection of Stage III melanoma who received adjuvant first-line checkpoint inhibitor therapy were treated for up to 1 year with Pembrolizumab (αPD-1; MSD) or Nivolumab.
Clinical flow cytometry
Detailed step-by-step protocols for preparation and analysis (including specimen gating strategies) of clinical samples by flow cytometry are available through Protocol Exchange52. In brief, peripheral blood samples were collected into ethylenediaminetetraacetic acid (EDTA)-vacutainers by venepuncture and then delivered to the immune monitoring laboratory at ambient temperature. Pre-analytical samples were stored for up to 4 h at 4 °C until processing. Whole blood was stained with DuraClone reagents (Duraclone IM Phenotyping Basic Tube, B53309; Duraclone IM T cell Subsets Tube, B53328; Duraclone IM TCRs Tube, B53340; Duraclone IM Treg Tube, B53346; Duraclone IM B cells Tube, B53318; Duraclone IM Dendritic Cells Tube, B53351; all from Beckman Coulter, Krefeld, Germany). Data were recorded with a NaviosTM cytometer running Cytometry List Mode Data Acquisition and Analysis Software version 1.3 (Beckman Coulter). Blinded analyses were performed by an experienced operator using Kaluza version 2.1 according to gating strategies illustrated in Supplementary Figs. 2–8.
Detection of CMV-reactive T cells by flow cytometry
Detailed step-by-step protocols are available through Protocol Exchange53. Briefly, frozen PBMC from patients were thawed and resuspended in RPMI medium (ThermoFisher, Schwerte, Germany) supplemented with 5% heat-inactivated pooled, male-only human AB serum (ZKT Tübingen, Germany), 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mM Glutamax (ThermoFisher). Cells were plated in 96-well round-bottom plates at 1 × 106 cells in 150 µl/well then incubated at 37 °C with 5% CO2. After 6 h, cultures were stimulated with 5 µg/ml CMV Lysate (Origene) and αCD28/αCD49 for 18 h. In some conditions, cultures were treated with neutralising monoclonal antibodies against PD-1 (MAB10864, R&D) plus CTLA‐4 (MAB3254, R&D) at 5 µg/ml each or mouse IgG1 isotype control (MAB002, R&D) at a final concentration of 10 µg/ml. During the last 4 h of cell culture, protein secretion was blocked with Protein Transport Inhibitor Cocktail (ThermoFisher) containing Brefeldin A und Monensin. Cytokine production was then assessed by flow cytometry. Dead cells were excluded with ViaKrome-808 Fixable Viability Dye (Beckman Coulter). Staining was performed in Cell Staining Buffer (BioLegend) with 10% FcR Block (Miltenyi). Cells were fixed and permeabilised using the eBioscience IC Fixation Buffer and Permeabilization Buffer (eBiosciences, ThermoFisher). Data were recorded with a Cytoflex LXTM cytometer running CytoExpert Software (Beckman Coulter) and analysed using Kaluza version 2.1 (Beckman Coulter) according to the gating strategy shown in Supplementary Fig. 11.
18F-FDG PET/CT imaging
Hepatic glucose metabolism as a measure of liver inflammation34 was analysed retrospectively in all 32 patients who underwent pretreatment 18F-FDG positron emission tomography and computed tomography (PET-CT) imaging as part of routine tumour staging shortly before starting immunotherapy. After overnight fasting, whole-body PET acquisitions covering at least the trunk were started 60–90 min after i.v. injection of 18F-FDG (3 MBq per kg body weight) on a Biograph Sensation 16 LSO or Biograph mCT40 Flow PET/CT scanner (both Siemens Healthcare, Germany) and lasted 18–24 min depending on patient size. The same area was covered by a low-dose CT scan (tube current <50 mAs, tube voltage 120 kV) if no contrast agents were used. Otherwise 130 ml of AccupaqueTM 300 (GE Healthcare) was applied as intravenous contrast agent with consecutive full-dose CT acquisition (120 kV, <100 mAs). PET images (slice thickness 5 mm) were corrected for random coincidences, decay, scatter, and attenuation and reconstructed iteratively using vendor parameter presets. PET and CT images were checked for breathing artifacts and scaled to standardised uptake values (SUV). SUVmean Blood was measured in a thread-like region-of-interest (ROI) manually set into the aorta and SUVmean Liver in a spherical ROI in the right liver lobe using the program ROVER (Version v3.0.35, Helmholtz-Zentrum Dresden-Rossendorf, Germany). SUR was calculated as with correction for the distribution time T of 18F-FDG to the reference time T0 of 75 min post injection54: SUR = (T0/T) × (SUVmean liver / SUVmean blood).
Routine clinical investigations
Routine biochemical and haematological investigations were performed by an in-house accredited diagnostic laboratory (Institute of Clinical Chemistry and Laboratory Medicine, UKR). Virological investigations were conducted by an in-house accredited laboratory (Institute of Clinical Microbiology and Hygiene, UKR) following routine diagnostic procedures. CMV-reactive T cells were quantified by IFN-γ ELISPOT (Lophius, Germany) according to the manufacturer’s instructions in an accredited laboratory (UKR).
Statistics, data transformations and visualisation
Significance tests and curve-fitting were performed with GraphPad Prism 6.04 (GraphPad Software, Inc., La Jolla, USA) or SPSS® version 25 (IBM Analytics, New York, USA). As indicated, data were analysed using a two-tailed Mann–Whitney (M.W.) test, two-tailed Fisher’s exact test (F.E.), D’Agostino & Pearson’s normality test (K2), one-way or two-way ANOVA, two-tailed t-tests, log-rank survival analysis, receiver-operator characteristic (ROC) analysis or calculating pairwise Pearson correlations (R2). Where stated in the figure legends, p-values were adjusted for multiple comparison using Benjamini–Hochberg (B.H.) correction or Bonferroni correction, but otherwise no adjustment was made.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Peer Review File
Reporting Summary
Source data
Source Data
Supplementary information
The online version contains supplementary material available at 10.1038/s41467-021-21572-y.
Acknowledgements
The authors gratefully acknowledge the financial support of Bristol-Myers Squibb and the BMS Foundation (Award FA-19-009) in the form of unrestricted research grants. This study was partly supported by grants from the German Research Foundation to S.H. (DFG HA 8481/1-1) and J.A.H. (DFG HU 1838/1-1; DFG HU 1838/2-1). L.C. is a Marie Skłodowska-Curie Research Fellow affiliated with INsTRuCT and receives funding from the European Union’s Horizon 2020 research and innovation programme (Award 860003). The authors thank Dr. Michael Kapinsky of Beckman Coulter GmbH for advice and support with clinical flow cytometry. The authors also thank Prof. Tobias Pukrop and staff of the Interdisciplinary Center for drug Tumor Therapy (ICT) for supporting collection of clinical samples. This work would not have been possible without the outstanding technical support of Erika Ostermeier, Marina Sorokina, Veronika Menath, Anke Hofmann and Joachim Schweimer.
Author contributions
J.A.H. designed the immune monitoring studies and other experiments, analysed the results and wrote the manuscript; K.K. organised and performed immune monitoring studies; P.R. designed and performed the experiments; J.J.W., J.K. and B.S. performed the virological analyses; K.E. provided expert histopathological descriptions; M.S., L.B. and D.H. performed the radiological and molecular imaging analyses; G.G., F.Z. and R.S. provided expert statistical and bioinformatics advice; L.C. quality-checked the manuscript; C.B. and R.B. were responsible for the routine clinical laboratory analyses; M.M. and K.D. provided the biological samples; H.L.S. and F.B. performed the experiments; H.J.S. provided infrastructural support; E.K.G., J.M.W. and S.H. provided material support, patient samples and critical feedback throughout the project. All authors approved the final version of the manuscript.
Data availability
Data supporting the findings of this study are available within the article and its Supplementary information files, or are available from the corresponding author subject to legal restrictions governing use of personal information. Source data are provided with this paper.
Competing interests
S.H. declares he has received consulting fees and speaker’s honoraria from BMS and Merck Sharp & Dohme (MSD). All other authors declare no competing interests.
Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ESCALATING DOSES | DrugDosageText | CC BY | 33664251 | 19,603,137 | 2021-03-04 |
What was the outcome of reaction 'Hepatitis'? | Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis.
Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.
Introduction
Treatment with anti-programmed cell death protein-1 (αPD-1) alone or combined with anti-cytotoxic T-lymphocyte-associated protein 4 (αCTLA-4) has greatly improved the prognosis of metastatic melanoma with a substantial fraction of patients achieving long-lasting partial or complete clinical responses1–6. The principal limitation of αPD-1/αCTLA-4 dual therapy is the relatively high rate of immune-related complications, which commonly include colitis, hepatitis and thyroiditis, but may also include pneumonitis, myocarditis and encephalitis7,8. Such adverse events range from mild reactions to life-threatening presentations, but are nevertheless clinically significant incidents that influence patient management9,10. Avoidance of complications has led to a somewhat complicated treatment decision-making process (Fig. 1a) that seeks to balance individual risk and capacity to tolerate adverse reactions against the superior clinical responses achieved with dual αPD-1/αCTLA-4 therapy over αPD-1 monotherapy11–13.Fig. 1 Individual predisposition to hepatitis after αPD-1/αCTLA-4 treatment.
a Individualised treatment of melanoma is guided by tumour staging, presence of B-RAF mutations and fitness-for-toxicity. b Colitis, hepatitis and thyroiditis are common immune-related complications of dual therapy with Nivolumab plus Ipilimumab; 31.4% of patients experienced two or more of these immune-related adverse reactions (n = 89). c Colitis, hepatitis and thyroiditis occurred independently and were not significantly associated with clinical response (n = 89; F.E). d–h Patients who developed hepatitis of any grade following dual therapy lacked biochemical signs of liver inflammation before treatment. In particular, no clinically meaningful differences in plasma levels of d aspartate transaminase (AST; n = 87; M.W.; Bonferroni-corrected p-value, m = 5), e alanine transaminase (ALT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), f gamma glutamyl transaminase (γ-GT; n = 89; M.W.; Bonferroni-corrected p-value, m = 5), g total bilirubin (n = 87; M.W.; Bonferroni-corrected p-value, m = 5), or h C-reactive protein (CRP; n = 85; M.W.; Bonferroni-corrected p-value, m = 5) were observed between patients who developed hepatitis and those who did not. Median values are indicated by a red line. i, j Biochemical markers of tumour burden were not different between patients who developed hepatitis and those who did not. i Pre-treatment levels of lactate dehydrogenase (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. j Pre-treatment levels of protein S100 (n = 89; M.W.; Bonferroni-corrected p-value, m = 4). k–m No association was observed between seropositivity for k hepatitis B virus core antigen (HBcAg; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), l hepatitis C virus (HCV; n = 85; F.E.; Bonferroni-corrected p-value, m = 3), or m hepatitis E virus (HEV; n = 67; F.E.; Bonferroni-corrected p-value, m = 3) and development of hepatitis following dual therapy. n No association was observed between rounds of αPD-1/αCTLA-4 administered and development of hepatitis (n = 89; M.W.).
Our aetiological understanding of colitis, hepatitis and thyroiditis caused by immune checkpoint blockade remains incomplete14; however, these treatment-related conditions are clearly different from known autoimmune diseases15,16. Such adverse reactions are usually attributed to generalised dysregulation of T cells17,18 or autoantibodies15. Here, we explore a different view—namely, that individual patients are predisposed to particular treatment-related complications by virtue of pathogen-specific memory T cells present in their repertoire before immune checkpoint blockade is given.
Cytomegalovirus (CMV) seroprevalance amongst European adults is over 50%. Primary CMV infection usually presents during young adulthood as an acute febrile illness, after which life-long latency is established. The exact sites and mechanisms of CMV latency are not fully resolved, but myelomonocytic cells in blood and tissues are major reservoirs19. CMV reactivation characteristically follows immune compromise caused by immunosuppressive therapy or other viral infections20. Clinical manifestations of CMV reactivation are variable, ranging from classic febrile illness to tissue-invasive disease presenting as colitis, hepatitis, pneumonitis or encephalitis21. Reactivation of CMV causes cellular injury through the cytopathic effect of viral replication, but more conspicuously through triggering T cell immunity. Pneumonitis in transplant recipients illustrates how CMV-reactive T cells provoke extensive, life-threatening inflammation despite low-level viral replication22. Even in anatomical locations from which T cells are normally excluded, such as the retina, T cell-mediated responses significantly contribute to CMV-related disease. Thus, low-level and compartmentalised reactivation of CMV can be responsible for serious acute immunopathology in humans23–25.
Cycles of CMV latency and reactivation lead to a now well-recognised phenomenon of memory inflation, which is typified by failure of primed CMV-specific CD8+ T cell populations to contract and give rise to central memory T cells26. Instead, a dominant pool of effector memory CD8+ T cells that does not become functionally exhausted is maintained27. Such inflationary CD8+ T cells achieve high frequencies over time, sustained through repetitive stimulation by viral reactivation or long-term persistence of viral antigens28. Memory inflation is described as an exclusive feature of CD8+ effector T cell responses, although durable expansion of CMV-specific CD4+ T cells can occur in transplant recipients29.
This study identifies pre-therapy expansion of CD4+ effector memory T cells (TEM) in CMV-infected patients with metastatic melanoma as a prognostic marker of αPD-1/αCTLA-4-related hepatitis. Opting for αPD-1 monotherapy or prophylactic valganciclovir in CMV IgG+ patients with unresectable metastatic disease and pre-treatment expansion of CD4+ TEM cells reduces their risk of hepatitis. We conclude that sub-clinical reactivation of CMV plays a previously unsuspected role in the immunopathogenesis of αPD-1/αCTLA-4-related hepatitis in a subgroup of patients.
Results
Clinical features do not predict αPD-1/αCTLA-4-related hepatitis
If immune-related complications of αPD-1/αCTLA-4 therapy resulted solely from treatment-induced immunological effects30,31, we might expect hepatitis, colitis and thyroiditis to coincide often32 (Fig. 1b). However, no such associations were found in a cohort of 89 patients with metastatic melanoma treated with αPD-1/αCTLA-4 dual therapy (Fig. 1c, Supplementary Fig. 1 and Supplementary Tables 1–3). This raises the possibility that some individuals are predisposed to particular adverse reactions.
In this study, we focused on factors that predispose to αPD-1/αCTLA-4-related hepatitis. Except for patients who developed hepatitis being generally younger (Supplementary Table 4) no associations were found between incidence of hepatitis and pre-treatment clinical variables (Supplementary Tables 4 and 5). Conventional biochemical markers of liver dysfunction, systemic inflammation or tumour burden did not discriminate between patients who did or did not develop hepatitis (Fig. 1d–j). We found no associations between incidence of hepatitis and seropositivity for hepatitis B virus (HBV), hepatitis C virus (HCV) or hepatitis E virus (HEV; Fig. 1k–m). Incidence of hepatitis was not greater with more rounds of αPD-1/αCTLA-4 therapy; in fact, as immune-related complications are reason to withhold treatment, patients who developed hepatitis tended to receive fewer rounds of αPD-1/αCTLA-4 (Fig. 1n). Autoimmune hepatitis-related autoantibodies were not associated with risk of hepatitis (Supplementary Table 6). In short, case history and routine clinical investigations did not predict hepatitis after dual therapy in our study cohort.
CD4+ TEM cell expansion predicts αPD-1/αCTLA-4-related hepatitis
We next profiled circulating leucocyte subsets immediately prior to start of dual therapy in a training set of n = 44 patients with unresectable metastatic melanoma (Supplementary Figs. 2–8). Comparing the frequency of 50 principal leucocyte subsets between patients who subsequently did (n = 18) or did not (n = 26) develop hepatitis revealed significant over-representation of CD4+ TEM cells associated with hepatitis (Fig. 2a, b). This observation was confirmed in a validation set (n = 45) of similar patients (Fig. 2c). Baseline expansion of CD4+ TEM cells was a fair discriminator (AUROC = 0.706) of patients who did or did not later develop hepatitis in the validation set (Fig. 2d). Strikingly, CD4+ TEM cell frequencies in all patients with completely resected disease were normally distributed with no extreme cases of baseline CD4+ TEM cell expansion, allowing us to set a threshold below which 99% of patients should fall (Fig. 2e). Applying this stringent cut-off to our validation cohort of patients with unresectable metastatic disease (Fig. 2f) allowed us to correctly predict hepatitis in 6 of 6 patients with CD4+ TEM≥21% (specificity = 100%) and correctly identify 6 of 20 patients who developed hepatitis (sensitivity = 30.0%). CD4+ TEM≥21% patients were not predisposed to colitis (Fig. 2g), thyroiditis or superior clinical responses to therapy (Supplementary Table 7). Hepatitis was not more severe in CD4+ TEM≥21% patients compared to CD4+ TEM<21% patients (Fig. 2h) and no difference in time-to-first presentation was observed (Fig. 2i). Hence, baseline CD4+ TEM expansion is a specific, but relatively insensitive prognostic marker of individuals who are predisposed to hepatitis after αPD-1/αCTLA-4 therapy. Owing to its low sensitivity, classifying patients as CD4+ TEM<21% has limited clinical utility; however, specifically identifying cases at high-risk of hepatitis before treatment is useful from a research perspective because we can then prospectively study the immunological basis of their predisposition.Fig. 2 Circulating CD4+ T effector memory cell frequency predicts hepatitis after Nivolumab plus Ipilimumab treatment.
a Peripheral blood samples were collected from melanoma patients with metastatic disease receiving αPD-1/αCTLA-4 therapy immediately before administration of the first dose (n = 89). Leucocyte subsets differentially represented in patients with or without hepatitis were identified in a randomly assigned training set (B.H.-corrected t-tests; n = 44; m = 50; FDR = 0.25). Red dots indicate significantly differently represented subsets. Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. b CD4+ TEM % in training set patients with or without treatment-related hepatitis (n = 44; M.W.). Median values are indicated by a red line. c CD4+ TEM % in validation set patients with or without treatment-related hepatitis (n = 45; M.W.). d ROC analysis of CD4+ TEM % as a discriminatory marker for treatment-related hepatitis in the validation set (n = 45). e Comparison of the bimodal distribution of CD4+ TEM % in patients with unresectable metastatic disease (n = 107) and the normal distribution (n = 49; K2 = 2.79; p = 0.248) of CD4+ TEM % in patients with completely resected tumours. A cut-off of CD4+ TEM ≥ 21% was set (indicated by a dashed red line) below which 99% of completely resected tumour cases should fall. Four pink points represent CD4+ TEM≥21% patients with metastatic disease who were electively treated with αPD-1 monotherapy. f In the validation set, 68.9% patients were correctly classified using a cut-off of CD4+ TEM ≥ 21 %, whereas 55.6% were correctly classified under the no-information model (n = 45; F.E.). g CD4+ TEM ≥ 21 % is not a marker of predisposition to αPD-1/αCTLA-4-related colitis (n = 89; F.E.). h CD4+ TEM≥21% patients did not experience more severe hepatitis than CD4+ TEM<21% patients (n = 38; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. i Time-to-first presentation of hepatitis was not different between CD4+ TEM≥21% (n = 12) and TEM<21% (n = 26) patients (log-rank). j Twelve of 12 patients with unresectable metastatic melanoma and CD4+ TEM ≥ 21% developed hepatitis after αPD-1/αCTLA-4 dual therapy. By contrast, 3 of 4 CD4+ TEM≥21% patients treated with αPD-1 monotherapy did not develop hepatitis (F.E.; p = 0.007).
Opting for αPD-1 monotherapy reduces risk of hepatitis
Although αPD-1 monotherapy achieves fewer sustained clinical responses in patients with metastatic melanoma, it causes fewer adverse reactions than αPD-1/αCTLA-4 dual therapy1. Therefore, there is a clear rationale for avoiding αPD-1/αCTLA-4 dual therapy in patients at risk of hepatitis. Four CD4+ TEM≥21% patients with metastasic disease presented during our study, but were electively treated with αPD-1 monotherapy (Fig. 2j). Whereas 12 of 12 CD4+ TEM≥21% patients treated with αPD-1/αCTLA-4 dual therapy developed hepatitis, 3 of 4 CD4+ TEM≥21% patients who received αPD-1 monotherapy remained hepatitis free. Reducing the incidence hepatitis by opting for αPD-1 monotherapy hints that CTLA-4 blockade may be mechanistically important for development of hepatitis in CD4+ TEM≥21% patients33.
CD4+ TEM frequency is an independent predictor of hepatitis
We next investigated possible causes of baseline CD4+ TEM expansion. To establish CD4+ TEM expansion as an independent risk factor, we first sought to exclude possible confounding covariables. Baseline CD4+ TEM≥21% was not related to sex, age or body-mass index (Supplementary Table 7 and Fig. 3a, b). No significant correlation was observed between baseline CD4+ TEM % and serum levels of C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT) or total bilirubin (Fig. 3c–g). Because glucose metabolism provides a reliable measure of liver inflammation34, we were able to further rule out liver inflammation prior to therapy as a predisposing cause of CD4+ TEM≥21% hepatitis by estimating hepatic glucose uptake in patients who underwent 18F-fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT studies as part of routine tumour staging shortly before starting immunotherapy (Fig. 3h). This retrospective comparison showed 18F-FDG standard uptake ratios (SURmean liver) were higher in CD4+ TEM<21% patients than CD4+ TEM≥21% patients with hepatitis (Fig. 3i). Therefore, our biochemical and radiological investigations argue against pre-treatment liver inflammation as a common cause for baseline CD4+ TEM expansion and treatment-related hepatitis.Fig. 3 CD4+ TEM frequency is an independent predictor of αPD-1/αCTLA-4-related hepatitis.
a CD4+ TEM % did not correlate with age (n = 89; Pearson). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM % did not correlate with body mass index (n = 89; Pearson). c CD4+ TEM % did not correlate with C-reactive protein (CRP) levels (n = 85; Pearson). d CD4+ TEM % did not correlate with aspartate aminotransferase (AST) levels (n = 87; Pearson). e CD4+ TEM % did not correlate with alanine aminotransferase (AST) levels (n = 89; Pearson). f CD4+ TEM % did not correlate with gamma-glutamyltransferase (γ-GT) levels (n = 89; Pearson). g CD4+ TEM % did not correlate with total bilirubin levels (n = 89; Pearson). h Glucose metabolism measured by 18F-fluoro-2-deoxy-d-glucose (18F-FDG) uptake in PET/CT studies is a quantitative marker of liver inflammation. Calculating standard uptake ratio (SURmean Liver) allows accurate quantification of 18F-FDG uptake in liver by correcting for differential clearance of tracer from blood and liver parenchyma. Higher SURmean Liver values indicate more severe inflammation. T0 = reference time point at 75 min post-injection and T = actual scan time. i SURmean Liver was lower in CD4+ TEM≥21% patients than CD4+ TEM<21% patients who developed hepatitis indicating less inflammation at baseline in the CD4+ TEM≥21% subgroup (n = 28; Pearson). j CD4+ TEM≥21% was not associated with the number of organs containing one or more metastases ≥1.5 cm in diameter (n = 103; F.E.). k CD4+ TEM≥21% was not associated with the presence of hepatic metastases (n = 103; F.E.). l CD4+ TEM % did not correlate with lactate dehydrogenase (LDH) levels (n = 88; Pearson). m CD4+ TEM % did not correlate with protein S100 levels (n = 88; Pearson). n CD4+ TEM≥21% was not associated with any prior therapy (n = 89; F.E.).
Because CD4+ TEM expansion is principally a feature of metastatic melanoma (Fig. 2e), we next asked whether CD4+ TEM% was somehow associated with tumour burden. No relationship was found between CD4+ TEM% and the number of organs containing metastases, presence of hepatic metastases or serum lactate dehydrogenase (LDH) and protein-S100 serum levels (Fig. 3j–m and Supplementary Table 7). There was a tendency for CD4+ TEM≥21% patients to have received previous therapy of any type (including BRAFi/MEKi or Talimogen laherparepvec) but besides implying a longer disease course before starting dual therapy, we see no mechanistic interpretation because these drugs share no common pharmacological action (Fig. 3n). In short, we found no obvious clinical association to explain the predisposition of CD4+ TEM≥21% patients to hepatitis.
CD4+ TEM cell expansion is associated with chronic T cell activation
Although CD4+ T cell counts were not different between CD4+ TEM<21% and CD4+ TEM≥21% patients (Supplementary Table 7), there were significantly fewer circulating naïve T cells in CD4+ TEM≥21% patients (Fig. 4a). This reduction was complemented by increased absolute numbers of CD4+ TEM and TEMRA cells (Fig. 4b, c) whereas central memory T cell (TCM) counts tended to be lower in CD4+ TEM≥21% patients (Fig. 4d). We next defined other leucocyte subsets that correlated with CD4+ TEM % in both our training and validation cohorts (Fig. 4e). Most covariant populations were T cells, particularly CD4+ T cell subsets. Changes in the CD4+ T cell compartment of TEM≥21% patients were consistent with chronic activation, particularly downregulation of CD27 and upregulation of CD57, HLA-DR and CD279 expression (Fig. 4f–i). Similar differences were detected in CD8+ T cells (Supplementary Fig. 9). Notably, CD4+ TEM≥21% patients tended to have higher frequencies of CD160+ CD244+ exhausted CD8+ T cells than CD4+ TEM<21% patients (Fig. 4j).Fig. 4 CD4+ TEM cell enrichment is associated with chronic activation and increased numbers of effector memory CD4+ T cells.
a–d Increased CD4+ TEM frequency before treatment reflects a decrease in circulating naïve CD4+ T cells and an increase in circulating numbers of CD4+ TEM cells. a Baseline naïve CD4+ T cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 5.2 ⨯ 10−5). b Baseline CD4+ TEM cell counts (n = 103; M.W.; Bonferroni correction: m = 4, p = 8.0 ⨯ 10−4). c Baseline CD4+ TEMRA cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). d Baseline CD4+ TCM cell counts (n = 103; M.W.; Bonferroni-corrected p-value, m = 4). Median values are indicated by a red line. e Pairwise correlations between CD4+ TEM cell frequency and other leucocyte subset frequencies in the training and validation sets (n = 103; Pearson). Example gating strategies for analysis of flow cytometry data are provided as Supplementary Figs. 2–8. f Baseline CD27+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.2 ⨯ 10−10). g Baseline CD57+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 2.0 ⨯ 10−9). h Baseline HLA-DR+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni correction: m = 60, p = 4.1 ⨯ 10−5). i Baseline CD279+ CD4+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). j Baseline CD160+ CD244+ CD8+ T cell frequencies (n = 103; M.W.; Bonferroni-corrected p-value, m = 60). k Baseline Torque Teno Virus (TTV) loads. Uninfected patients were censored from analysis (n = 74; M.W.; Bonferroni-corrected p-value, m = 60). Median values are indicated by a red line.
Most adults are persistently infected with Torque Teno Virus (TTV), a non-enveloped, circular, single-stranded DNA virus of the Anellovirus family that causes no apparent disease. T cell immunity controls TTV replication in healthy people, whereas TTV copy number in immunocompromised individuals is increased; therefore, TTV load in plasma is a useful marker of immune competence. Despite accumulating chronically activated and exhausted T cells, TTV load in CD4+ TEM≥21% versus CD4+ TEM<21% patients was not different, implying that CD4+ TEM≥21% patients are not generally immunocompromised (Fig. 4k).
CD4+ TEM cell expansion correlates with immunity to CMV
To briefly summarise, baseline expansion of CD4+ TEM cells identifies a subset of patients with metastasic melanoma who are predisposed to αPD-1/αCTLA-4-related hepatitis. These patients show signs of persistent or recurrent CD4+ and CD8+ T cell responses35, but are otherwise clinically and immunologically unremarkable. It is usually very difficult to isolate factors responsible for such a non-specific immunological picture36. Fortunately, a surprising pattern emerged from our dataset: CD4+ TEM≥21% patients mostly presented between September and February (Fig. 5a). This seasonal influence was apparent over all 4 years of the study, leading us to think that CD4+ TEM expansion might be driven by a pathogen. Active infections with hepatitis viruses, including HBV and HCV, are relative contraindications to αPD-1/αCTLA-4 therapy (Supplementary Table 7), so we were forced to consider possible involvement of other hepatotropic viruses, such as HEV and herpesgroup viruses.Fig. 5 CD4+ TEM cell expansion correlates with immunity to cytomegalovirus.
a Seasonal presentation of CD4+ TEM≥21% patients between 2017 and 2020 (n = 103; F.E.). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. b CD4+ TEM≥21% status was associated with high serum levels of anti-CMV IgG antibodies (n = 100; F.E.; p = 1.2 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. c CD4+ TEM≥21% status was associated with CMV-reactivity in pp65 ELISPOT (n = 53; F.E.; p = 9.0 ⨯ 10−5). Dashed red line indicates a cut-off of CD4+ TEM ≥ 21%. d Development of hepatitis was associated with CMV-seropositivity and CD4+ TEM≥21% status (n = 89). Median values are indicated by a red line. e ROC analysis showing CD4+ TEM % is a superior discriminator of patients at risk of hepatitis when considering only CMV IgG+ cases as opposed to all cases. f Classification of patients with unresectable metastatic melanoma who did or did not develop αPD-1/αCTLA-4-related hepatitis according to CMV IgG status and baseline CD4+ TEM cell frequency using a revised cut-off of CD4+ TEM ≥ 16%. Red boxes indicate 34 of 40 (85%) cases correctly classified by our model (n = 40; F.E.; p = 1.4 ⨯ 10−5). Green box indicates 2 of 17 (11.7%) cases predicted to develop hepatitis who did not. Pink box indicates 4 of 23 (17.4%) cases predicted not to develop hepatitis who did. Blue box indicates 19 of 49 CMV IgG− patients not considered by our model who developed hepatitis.
Latent CMV infection is prevalent amongst European adults and involves many organs, including liver. Compartmentalised reactivation of CMV infection occurs in immunocompromised individuals and those with concomitant viral upper respiratory tract infections20. In our patients, we found a strong association between serum CMV-specific IgG antibody levels and CD4+ TEM status (Fig. 5b). Furthermore, T cell reactivity against CMV pp65 peptides in an IFN-γ enzyme-linked immunospot (ELISPOT) assay was tightly associated with CD4+ TEM status (Fig. 5c). These results led us to hypothesise a causal relationship between compartmentalised, sub-clinical CMV reactivation in liver and chronic enrichment of CD4+ TEM cells in blood.
Because baseline CD4+ TEM cell expansion was mainly a feature of CMV IgG+ patients (Fig. 5d), we next asked whether incorporating CMV IgG status could improve our predictive model. When considering only CMV IgG+ cases, CD4+ TEM % was a more discriminatory marker of hepatitis (Fig. 5e). Therefore, using our training set filtered for CMV IgG+ cases, we revised our cut-off to CD4+ TEM ≥ 16% in CMV IgG+ cases in order to achieve a better compromise between specificity and sensitivity (Supplementary Fig. 10). The new cut-off performed well in the validation set with a correct classification rate of 81.0% (positive predictive value (PPV) = 85.7% and negative predictive value (NPV) = 78.6%) compared to 42.9% under the no-information model.
For descriptive purposes, we can consider the distribution of patients from the combined training and validation sets according to CMV IgG and CD4+ TEM status (Fig. 5f). Our predictive model explains the occurrence of hepatitis in 34 of 89 (38.2%) of all patients (red boxes). Two of 17 (12%) CMV IgG+ CD4+ TEM≥16% patients (green box) did not develop hepatitis: one of these received four rounds of αPD-1/αCTLA-4 therapy and registered no complications; however, the other received only 1 round of αPD-1/αCTLA-4 before treatment with prednisolone from weeks 2 to 7 for colitis. We speculate 4 of 23 CMV IgG+ CD4+ TEM<16% patients who were incorrectly predicted as hepatitis-negative (pink box) were sampled at an early stage of CD4+ TEM cell expansion and our test was not sensitive enough to discriminate the change. Our model does not explain why 19 of 49 CMV IgG− patients developed hepatitis (blue box) but we believe these represent an aetiologically distinct subset.
CMV-reactive CD4+ T cells are enriched in CD4+ TEMhigh patients
We next asked whether CMV-reactive CD4+ T cells were enriched in patients with baseline CD4+ TEM expansion. Peripheral blood mononuclear cells (PBMC) were stimulated in culture for 18 h with CMV lysates before IFN-γ, TNFα, IL-17, IL-4 and CD69 expression was measured by flow cytometry (Fig. 6a and Supplementary Figs. 11 and 12). To detect hyporesponsive CMV-specific T cells, paired cultures were also stimulated in the presence of neutralising antibodies against PD-1 and CTLA-4. In contrast to CMV IgG− and CMV IgG+ CD4+ TEM<16% patients, we readily detected IFN-γ-producing, CMV-reactive CD4+ T cells in CMV IgG+ CD4+ TEM≥16% patients (Fig. 6b). This difference implies a higher number of circulating IFN-γ-producing, CMV-reactive CD4+ T cells (Fig. 6c). Proportions of CMV-reactive CD4+ T cells expressing IL-17, IL-4 or only TNFα were too low to quantify accurately.Fig. 6 CMV-reactive CD4+ T cells are enriched in patients with CD4+ TEM cell expansion.
CMV-reactive CD4+ T cells in patients with unresectable metastatic melanoma were assayed by in vitro stimulation with CMV lysates (blue boxes). Neutralising antibodies (red hatching) were used to detect T cells unable to respond to CMV antigens owing to expression of PD-1 or CTLA-4. T cell responses were quantified by flow cytometry analysis of cytokine expression. a Example data from a CMV IgG+ CD4+ TEM≥16% patient who developed hepatitis. Gating of live, singlet, IFN-γ-producing CD4+ T cells is illustrated in Supplementary Fig. 11. b Frequencies of IFN-γ-producing CD4+ T cells in patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers. c Absolute numbers of circulating IFN-γ-producing CD4+ T cells patients categorised according to CMV IgG serostatus and baseline CD4+ TEM frequency (n = 42; two-way ANOVA with Tukey correction for multiple comparisons; n.s. = not significant). Boxplots represent the median, 25th and 75th percentiles, and Tukey whiskers.
Valganciclovir reverses αPD-1/αCTLA-4-related hepatitis
Strong associations between T cell immunity against CMV, expansion of CD4+ TEM and risk of treatment-related hepatitis imply an underlying pathogenic mechanism; however, to demonstrate a causal relationship, we needed to establish that inhibiting CMV replication was effective in treating or preventing hepatitis. Valganciclovir is an anti-viral agent licensed for therapy and prophylaxis of CMV infections in immunocompromised patients. It is a widely used and safe drug with a well-known and broadly acceptable profile of adverse effects. Therefore, we next gave valganciclovir treatment to two patients with αPD-1/αCTLA-4-related hepatitis.
The first patient was a comparatively fit 54-year-old man with a new diagnosis of metastatic melanoma (Fig. 7a). Staging CT revealed multiple lung and bone metastases, but no metastasis to liver or lymph nodes. At baseline, the patient was CMV-IgG+ and CD4+ TEM = 18.7% (Fig. 7b). Nivolumab plus Ipilimumab were given at 0, 3 and 6 weeks. A fourth round of αPD-1/αCTLA-4 at week 9 was omitted owing to joint pain and the patient received two rounds of Denosumab (αRANKL). Nivolumab monotherapy was administered in weeks 12, 16, 20 and 24. Staging CT at week 14 showed a partial clinical response with significant regression of pulmonary metastases; hence, checkpoint blockade was of clear clinical benefit.Fig. 7 Case 1: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 54-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction, withdrawal and re-introduction of valganciclovir treatment. c The patient presented at the end of week 40 with recrudescent hepatitis and was treated with 900 mg/day valganciclovir for 2 days prior to liver biopsy. Histopathological image of the liver biopsy (H&E staining; scale bar 500 µm). d Generally, the liver parenchyma appeared normal (H&E staining; scale bar 100 µm). e Only a few lymphocytes and sparse necrotic hepatocytes were observed in portal areas with small bile plugs (arrows) with no signs of hepatitis (H&E staining; scale bar 100 µm).
The patient received a dose of αPD-1 monotherapy in week 32. Four weeks later, he presented in clinic with grade 4 hepatitis. Strong reactions against pp65 and IE-1 peptides were measured by ELISPOT. Accordingly, the patient was treated with 900 mg/day valganciclovir plus prednisolone. Liver function tests (LFTs) returned to normal, so over the subsequent 2 weeks, prednisolone was weaned and then valganciclovir was withdrawn. Seven days later, the patient returned to clinic with deranged LFTs. Valganciclovir and prednisolone were both reinstated, leading to a rapid normalisation of LFTs. Two days later, a for-cause liver biopsy was performed (Fig. 7c–e). The tissue was essentially normal, although a few dying hepatocytes and isolated lymphocytes were observed in the portal areas. Immunohistochemical staining for CMV and nested CMV PCR from fixed biopsy material were negative. The patient remained clinically stable for 9 days, so he was again weaned from prednisolone by the start of week 43; however, on this occasion, 900 mg/day valganciclovir treatment was continued. After complete withdrawal of prednisolone, while still receiving valganciclovir, the patient’s LFTs remained stable for a further 4 weeks. At the start of week 47, valganciclovir was withdrawn for a second time. Subsequently, the patient did not develop hepatitis and required no further steroids. The patient received further doses of αPD-1 monotherapy in weeks 54 and 58 without signs of recurrent liver injury. To us, this suggests the T cell antigens driving hepatitis in this patient were absent after valganciclovir treatment. In our clinical opinion, despite the absence of detectable virus, the patient’s fast recovery and unusual relapse of hepatitis are best explained by introduction, withdrawal and reintroduction of valganciclovir.
The second patient was a 49-year-old man who had an uncomplicated first year after αPD-1/αCTLA-4 and had been receiving Encorafenib/Binimetinib therapy for 7 weeks when he developed hepatitis in week 67 (Fig. 8a, b). Hepatitis failed to resolve despite withdrawal of B-RAFi/MEKi and escalating doses of prednisolone. 900 mg/day valganciclovir was introduced at the start of week 72 and a for-cause biopsy was performed on the same day (Fig. 8b). Four days later, the patient started a course of 1 mg/day mycophenolate mofetil. Strikingly, AST, ALT and γ-GT levels declined consistently from the day after valganciclovir was given, although total bilirubin continued to rise. Starting valganciclovir treatment appeared to be temporally related to increased reactivity in CMV IE-1 ELISPOT and a small decline in CD4+ TEM frequency.Fig. 8 Case 2: valganciclovir treatment of late-onset αPD-1/αCTLA-4-related hepatitis.
A 49-year-old male patient who received αPD-1 (Nivolumab) plus αCTLA-4 (Ipilimumab) dual therapy for metastatic melanoma presented with late-onset hepatitis. a Course of treatment. b Change in hepatitis-related parameters over time and their association with introduction of valganciclovir treatment. c Histopathological image of a liver biopsy taken at the start of week 72 showing signs consistent with drug toxicity, autoimmunity or viral infection (H&E staining; scale bar 500 µm). d Extensive centrilobular necrosis (arrows) involving 30–40% of hepatocytes was observed (H&E staining; scale bar 100 µm). e Dense inflammatory infiltration of lymphocytes, eosinophils and neutrophils was seen in portal areas (H&E staining; scale bar 100 µm).
Liver biopsy revealed dense infiltration by lymphocytes, eosinophils and neutrophils with an accompanying ductal reaction (Fig. 8c–e). Extensive centrilobular hepatocyte necrosis was observed, which was also associated with inflammatory infiltration. These histopathological signs of significant liver damage could have been consistent with autoimmunity or viral infection. Both histological staining for CMV and CMV PCR from fixed biopsy material were negative. Although we were unable to detect virus, it is our clinical impression that markers of liver damage responded to valganciclovir treatment.
Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis
We next asked whether valganciclovir prophylaxis could prevent αPD-1/αCTLA-4-related hepatitis in predisposed individuals. The 50th, 75th and 90th percentiles of time-to-hepatitis in CMV-IgG+ patients were 24, 52 and 84 days, respectively; therefore, we treated four CMV IgG+ CD4+ TEM≥16% patients receiving αPD-1/αCTLA-4 therapy with prophylactic valganciclovir for between 4 and 23 weeks (Fig. 9a). Two of these patients registered mild, transient transaminitis that resolved without treatment, so were not diagnosed with hepatitis. Hence, we observed no hepatitis in the four valganciclovir-treated patients, whereas 15 of 17 (88.2%) CMV IgG+ CD4+ TEM≥16% patients treated with αPD-1/αCTLA-4 and no valganciclovir prophylaxis developed clinical hepatitis (Fig. 9b). To us, these four cases are consistent with the idea that CMV plays an important aetiological role in development of hepatitis after αPD-1/αCTLA-4 therapy in a specific subset of patients.Fig. 9 Valganciclovir prophylaxis prevents αPD-1/αCTLA-4-related hepatitis.
a Heatmaps showing peak values of AST, ALT and bilirubin expressed as multiples of sex-adjusted upper limit of normal ranges. Fifteen of 17 (88.2%) patients classified as CMV IgG+ CD4+ TEM≥16% at baseline subsequently developed hepatitis. In contrast, 4 of 4 CMV IgG+ CD4+ TEM≥16% patients treated with 900 mg/day prophylactic valganciclovir remained hepatitis free. b In four initial cases, prophylactic valganciclovir prevented development of hepatitis (n = 21; F.E.).
Discussion
Our study seeks to explain why a subset of patients with advanced melanoma is predisposed to hepatitis following immune checkpoint blockade. In our model, metastatic disease promotes compartmentalised CMV reactivation in latently infected individuals, possibly triggered by an unknown winter virus infection; in turn, CMV stimulates expansion of CD4+ TEM cells prior to immunotherapy. When αPD-1/αCTLA-4 therapy is given, these TEM cells might inflict liver injury directly or promote bystander T cell responses. We propose CMV-driven T cell responses are a single, but salient example of a general mechanism responsible for hepatitis after checkpoint blockade because other viruses or toxic agents could also drive chronic CD4+ T cell activation before therapy. We speculate anti-viral immunity might also explain predisposition to other adverse reactions following αPD-1/αCTLA-4 therapy, such as colitis or pneumonitis37. The remarkable overlap between organs affected by tissue-invasive CMV disease and those susceptible to immune-related adverse reactions has not escaped our attention38,39.
Being able to identify patients predisposed to hepatitis opens various possibilities for avoiding or preventing treatment-related hepatitis40. Three of four CD4+ TEM≥21% patients assigned to αPD-1 monotherapy instead of αPD-1/αCTLA-4-treatment did not develop hepatitis as predicted; therefore, baseline CD4+ TEM expansion could be taken as a relative contraindication to dual therapy. However, a more promising strategy is to suppress occult CMV reactivation. In our study, valganciclovir prophylaxis apparently prevented hepatitis in four of four CMV IgG+ CD4+ TEM≥16% patients. This approach must be refined in terms of dosing and duration of anti-viral therapy in randomised, controlled clinical trials, but could potentially achieve the superior outcomes of αPD-1/αCTLA-4 dual therapy over αPD-1 monotherapy with fewer complications.
Because baseline CD4+ TEM expansion was observed in patients with metastatic disease, but not in patients with fully resected melanoma, it is possible that disseminated melanoma promotes low-level CMV reactivation, perhaps through compromised T cell immunity, which then stimulates virus-specific CD4+ T cell expansion. The prominent association between CD4+ TEM expansion and CMV (in contrast to other herpesgroup virus infections) might simply reflect differences in tissue tropism and, we speculate, the capacity of compartmentalised CMV reactivation in liver to drive especially strong T cell responses. Seasonal variation in the incidence of CD4+ TEMhigh cases suggests that environmental factors influence expansion and contraction of the CD4+ TEM cell pool41,42. In particular, we suspect common winter viruses somehow promote CMV reactivation in liver.
Chronic, low-level exposure to viral antigens preferentially expands TEM over TCM43–49, so CMV-reactive CD4+ T cell expansion might be sustained by very little CMV replication. On-going T cell reactions against CMV in CD4+ TEMhigh patients are likely to suppress CMV replication almost completely. Our inability to detect CMV in baseline serum samples from CD4+ TEMhigh patients or liver biopsies from patients with high-grade hepatitis is a challenge for our theory; however, it may simply be beyond our technical capability to detect very low levels of compartmentalised viral reactivation. In our view, the strong correlation between CMV-specific immunity and development of hepatitis, as well as the apparent effectiveness of valganciclovir, suggests a causal role for CMV in the aetiology of αPD-1/αCTLA-4-related hepatitis.
We do not presently know whether CMV-specific CD4+ TEM cells inflict liver injury directly or provoke bystander T cell responses50. Administration of αPD-1 or αCTLA-4 has been associated with CMV reactivation in colon, so it is probable that CMV also reactivates in liver during dual therapy51. In two patients with high-grade hepatitis, we observed liver inflammation subsided immediately after starting valganciclovir. In our view, the likely presence of viral antigen and apparent responsiveness to valganciclovir is consistent with a direct pathological effect of CMV-specific T cells, although we accept this will be hard to prove in patients.
Better understanding the contribution of anti-viral T cell immunity to checkpoint blockade-related adverse reactions leads us to unexpected solutions for preventing serious complications of cancer immunotherapy. From a clinical perspective, the immunological mechanisms described illustrate how patients’ medical histories, especially prior exposure to pathogens, impact their experience of cancer and response to therapy.
Methods
Study approval and patient management
This study involving human research participants was performed in accordance with the Declaration of Helsinki and all applicable German and European laws and ethical standards. Specifically, specimens were obtained from patients with Stage III or IV melanoma participating in a single-centre observational clinical trial authorised by the Ethics Committee of the University of Regensburg (approval 16-101-0125) and registered with clinicaltrials.gov (NCT04158544). All participants gave full, informed written consent. The first reported patient was recruited in October 2016 and the last reported patient was recruited in July 2020. Patients received standard-of-care treatment according to local guidelines (Fig. 1a). Stage IV patients with unresectable metastatic disease who received first- or second-line checkpoint inhibitor therapy were initially treated with Nivolumab (αPD-1; Bristol-Myers Squibb) and Ipilimumab (αCTLA-4; Bristol-Myers Squibb) for four cycles, and thereafter with Nivolumab maintenance therapy (3 mg/kg at 3-week intervals). Those patients with complete resection of Stage III melanoma who received adjuvant first-line checkpoint inhibitor therapy were treated for up to 1 year with Pembrolizumab (αPD-1; MSD) or Nivolumab.
Clinical flow cytometry
Detailed step-by-step protocols for preparation and analysis (including specimen gating strategies) of clinical samples by flow cytometry are available through Protocol Exchange52. In brief, peripheral blood samples were collected into ethylenediaminetetraacetic acid (EDTA)-vacutainers by venepuncture and then delivered to the immune monitoring laboratory at ambient temperature. Pre-analytical samples were stored for up to 4 h at 4 °C until processing. Whole blood was stained with DuraClone reagents (Duraclone IM Phenotyping Basic Tube, B53309; Duraclone IM T cell Subsets Tube, B53328; Duraclone IM TCRs Tube, B53340; Duraclone IM Treg Tube, B53346; Duraclone IM B cells Tube, B53318; Duraclone IM Dendritic Cells Tube, B53351; all from Beckman Coulter, Krefeld, Germany). Data were recorded with a NaviosTM cytometer running Cytometry List Mode Data Acquisition and Analysis Software version 1.3 (Beckman Coulter). Blinded analyses were performed by an experienced operator using Kaluza version 2.1 according to gating strategies illustrated in Supplementary Figs. 2–8.
Detection of CMV-reactive T cells by flow cytometry
Detailed step-by-step protocols are available through Protocol Exchange53. Briefly, frozen PBMC from patients were thawed and resuspended in RPMI medium (ThermoFisher, Schwerte, Germany) supplemented with 5% heat-inactivated pooled, male-only human AB serum (ZKT Tübingen, Germany), 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mM Glutamax (ThermoFisher). Cells were plated in 96-well round-bottom plates at 1 × 106 cells in 150 µl/well then incubated at 37 °C with 5% CO2. After 6 h, cultures were stimulated with 5 µg/ml CMV Lysate (Origene) and αCD28/αCD49 for 18 h. In some conditions, cultures were treated with neutralising monoclonal antibodies against PD-1 (MAB10864, R&D) plus CTLA‐4 (MAB3254, R&D) at 5 µg/ml each or mouse IgG1 isotype control (MAB002, R&D) at a final concentration of 10 µg/ml. During the last 4 h of cell culture, protein secretion was blocked with Protein Transport Inhibitor Cocktail (ThermoFisher) containing Brefeldin A und Monensin. Cytokine production was then assessed by flow cytometry. Dead cells were excluded with ViaKrome-808 Fixable Viability Dye (Beckman Coulter). Staining was performed in Cell Staining Buffer (BioLegend) with 10% FcR Block (Miltenyi). Cells were fixed and permeabilised using the eBioscience IC Fixation Buffer and Permeabilization Buffer (eBiosciences, ThermoFisher). Data were recorded with a Cytoflex LXTM cytometer running CytoExpert Software (Beckman Coulter) and analysed using Kaluza version 2.1 (Beckman Coulter) according to the gating strategy shown in Supplementary Fig. 11.
18F-FDG PET/CT imaging
Hepatic glucose metabolism as a measure of liver inflammation34 was analysed retrospectively in all 32 patients who underwent pretreatment 18F-FDG positron emission tomography and computed tomography (PET-CT) imaging as part of routine tumour staging shortly before starting immunotherapy. After overnight fasting, whole-body PET acquisitions covering at least the trunk were started 60–90 min after i.v. injection of 18F-FDG (3 MBq per kg body weight) on a Biograph Sensation 16 LSO or Biograph mCT40 Flow PET/CT scanner (both Siemens Healthcare, Germany) and lasted 18–24 min depending on patient size. The same area was covered by a low-dose CT scan (tube current <50 mAs, tube voltage 120 kV) if no contrast agents were used. Otherwise 130 ml of AccupaqueTM 300 (GE Healthcare) was applied as intravenous contrast agent with consecutive full-dose CT acquisition (120 kV, <100 mAs). PET images (slice thickness 5 mm) were corrected for random coincidences, decay, scatter, and attenuation and reconstructed iteratively using vendor parameter presets. PET and CT images were checked for breathing artifacts and scaled to standardised uptake values (SUV). SUVmean Blood was measured in a thread-like region-of-interest (ROI) manually set into the aorta and SUVmean Liver in a spherical ROI in the right liver lobe using the program ROVER (Version v3.0.35, Helmholtz-Zentrum Dresden-Rossendorf, Germany). SUR was calculated as with correction for the distribution time T of 18F-FDG to the reference time T0 of 75 min post injection54: SUR = (T0/T) × (SUVmean liver / SUVmean blood).
Routine clinical investigations
Routine biochemical and haematological investigations were performed by an in-house accredited diagnostic laboratory (Institute of Clinical Chemistry and Laboratory Medicine, UKR). Virological investigations were conducted by an in-house accredited laboratory (Institute of Clinical Microbiology and Hygiene, UKR) following routine diagnostic procedures. CMV-reactive T cells were quantified by IFN-γ ELISPOT (Lophius, Germany) according to the manufacturer’s instructions in an accredited laboratory (UKR).
Statistics, data transformations and visualisation
Significance tests and curve-fitting were performed with GraphPad Prism 6.04 (GraphPad Software, Inc., La Jolla, USA) or SPSS® version 25 (IBM Analytics, New York, USA). As indicated, data were analysed using a two-tailed Mann–Whitney (M.W.) test, two-tailed Fisher’s exact test (F.E.), D’Agostino & Pearson’s normality test (K2), one-way or two-way ANOVA, two-tailed t-tests, log-rank survival analysis, receiver-operator characteristic (ROC) analysis or calculating pairwise Pearson correlations (R2). Where stated in the figure legends, p-values were adjusted for multiple comparison using Benjamini–Hochberg (B.H.) correction or Bonferroni correction, but otherwise no adjustment was made.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Supplementary Information
Peer Review File
Reporting Summary
Source data
Source Data
Supplementary information
The online version contains supplementary material available at 10.1038/s41467-021-21572-y.
Acknowledgements
The authors gratefully acknowledge the financial support of Bristol-Myers Squibb and the BMS Foundation (Award FA-19-009) in the form of unrestricted research grants. This study was partly supported by grants from the German Research Foundation to S.H. (DFG HA 8481/1-1) and J.A.H. (DFG HU 1838/1-1; DFG HU 1838/2-1). L.C. is a Marie Skłodowska-Curie Research Fellow affiliated with INsTRuCT and receives funding from the European Union’s Horizon 2020 research and innovation programme (Award 860003). The authors thank Dr. Michael Kapinsky of Beckman Coulter GmbH for advice and support with clinical flow cytometry. The authors also thank Prof. Tobias Pukrop and staff of the Interdisciplinary Center for drug Tumor Therapy (ICT) for supporting collection of clinical samples. This work would not have been possible without the outstanding technical support of Erika Ostermeier, Marina Sorokina, Veronika Menath, Anke Hofmann and Joachim Schweimer.
Author contributions
J.A.H. designed the immune monitoring studies and other experiments, analysed the results and wrote the manuscript; K.K. organised and performed immune monitoring studies; P.R. designed and performed the experiments; J.J.W., J.K. and B.S. performed the virological analyses; K.E. provided expert histopathological descriptions; M.S., L.B. and D.H. performed the radiological and molecular imaging analyses; G.G., F.Z. and R.S. provided expert statistical and bioinformatics advice; L.C. quality-checked the manuscript; C.B. and R.B. were responsible for the routine clinical laboratory analyses; M.M. and K.D. provided the biological samples; H.L.S. and F.B. performed the experiments; H.J.S. provided infrastructural support; E.K.G., J.M.W. and S.H. provided material support, patient samples and critical feedback throughout the project. All authors approved the final version of the manuscript.
Data availability
Data supporting the findings of this study are available within the article and its Supplementary information files, or are available from the corresponding author subject to legal restrictions governing use of personal information. Source data are provided with this paper.
Competing interests
S.H. declares he has received consulting fees and speaker’s honoraria from BMS and Merck Sharp & Dohme (MSD). All other authors declare no competing interests.
Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33664251 | 19,620,963 | 2021-03-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Post-mortem biopsy of a patient with late exacerbation of COVID-19 pneumonia.
Pathological findings of coronavirus disease (COVID-19) have rarely been reported owing to its contagious nature. Here, we treated an 82-year-old man whose condition was diagnosed as COVID-19 pneumonia, which exacerbated approximately 25 days after the initial onset. The patient died despite receiving intensive care. Post-mortem percutaneous needle biopsy of the lungs and liver tissue was performed, including genomic analysis, immunochemical tests, and pathological studies. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage. Supposedly, the organizing phase of acute respiratory distress syndrome (ARDS) induced COVID-19. Polymerase chain reaction (PCR) test and immunostaining of biopsy specimens showed negative results for COVID-19. Post-mortem percutaneous needle biopsy was more effective in reducing the risk of contagiousness than autopsy.
Introduction
Late in December 2019, an outbreak of infections caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was reported in Wuhan, Hubei Province, China [1]. The World Health Organization named the SARS‐CoV‐2 infection as coronavirus disease (COVID‐19). COVID‐19 instantly spread worldwide, thereby becoming a pandemic. The clinical features of COVID‐19 are diverse, ranging from asymptomatic to severe pneumonia and death [2]. Genome sequencing of the virus and development of therapeutic agents and vaccines have been researched worldwide; however, pathological findings of this disease have been scarcely reported because of its contagious nature (in humans) [3]. Here, we describe pathological findings detected through post‐mortem percutaneous needle biopsy of a patient with late‐onset severe pneumonia from COVID‐19.
Case Report
The patient was an 82‐year‐old man who presented with low‐grade fever and dry cough at another hospital, where he tested positive for COVID‐19 through a polymerase chain reaction (PCR) test. He was referred to our hospital with symptoms of COVID‐19 pneumonia. He had a history of diabetes and hypertension but did not smoke. Furthermore, he had been administered a calcium channel blocker and an angiotensin‐converting enzyme (ACE) inhibitor. Chest computed tomography (CT) revealed multicentric peripheral ground‐glass opacity (GGO), especially in the right lower lobe (Fig. 1A).
Figure 1 Summary of treatment progress. Chest CT images of the patient at different stages of COVID‐19. (A) Axial view of CT from the previous hospital (day 8) shows GGO predominantly spread on the right lower lobe. (B) Axial view of CT on intubation (day 33) shows GGO spread to bilaterally and consolidation on the right lower lobe. (C) Axial view of CT on post‐mortem autopsy imaging (day 60) shows bilateral spread of consolidation and bilateral pleural effusion. AC/PC, assist control/pressure control; AC/VC, assist control/volume control; APRV, airway pressure release ventilation; COVID‐19, coronavirus disease; CT, computed tomography; GGO, ground‐glass opacity; MPEM, meropenem; MR, muscle relaxant; NC, nasal cannula; NHF, nasal high flow; NO, nitric oxide; SP, spontaneous ventilation; TAZ/PIPC, tazobactam/piperacillin; TEIC, teicoplanin.
A summary of the treatment protocol is shown in Figure 1. We administered favipiravir and ciclesonide, alongside oxygen therapy. On day 18, peripheral oxygen saturation (SpO2) and dyspnoea improved, his fever subsided, and the oxygenation therapy was withdrawn. However, the PCR tests remained positive from days 20 to 25. On day 26, SpO2 worsened, his fever returned, and oxygen therapy was resumed. Although the culture test results were negative, antibiotics (tazobactam/piperacillin, TAZ/PIPC) were administrated empirically for suspected complications of secondary infection. The patient needed intubation on day 33. CT revealed consolidation of the right lower lobe around the GGO (Fig. 1B).
The patient received mechanical ventilation in airway pressure release ventilation mode. This was in addition to nitric oxide (NO) inhalation and methylprednisolone (60 mg/day) administration to counter acute respiratory distress syndrome (ARDS). Furthermore, we administered a muscle relaxant along with fentanyl and midazolam for sedation. The patient's condition worsened on day 42, despite providing intensive care. At this stage, blood culture revealed the presence of Escherichia coli, and Stenotrophomonas maltophilia was detected in the sputum culture, suggesting ventilation‐associated pneumonia. The patient died on day 60. Autopsy CT revealed bilateral lung consolidation along with bilateral pleural effusion (Fig. 1C). There was no obvious abscess in any organ.
After obtaining informed consent from his family, we performed post‐mortem percutaneous needle biopsies of the lungs and liver tissues with a 14‐G needle. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage (DAD) (Fig. 2). In the exudative phase of DAD, the lung tissues exhibited prominent hyaline membranes with minimal chronic inflammation, while those in the organizing phase showed intra‐alveolar fibrosis. In addition, they revealed intra‐alveolar haemorrhage and reactive type II pneumocytes. Vasculitis, thrombosis, and the other pathogens were absent. There was no obvious difference between the right and left lungs. In the liver, several micro‐abscesses due to sepsis were detected. Real‐time reverse transcription PCR and immunostaining of these biopsy specimens for COVID‐19 were performed by the Department of Pathology, National Institute of Infectious Disease in Japan [4], all of which were negative. On the basis of the above‐mentioned histopathological and genomic analyses, we considered that the cause of death was ARDS due to cytokine storm, and immune responses, rather than secondary infection or other factors, induced COVID‐19.
Figure 2 Histopathology of the patient's post‐mortem percutaneous needle lung biopsy sample. (A) Diffuse alveolar damage (DAD) with hyaline membranes (→), intra‐alveolar haemorrhage, and reactive type II pneumocytes (▸) (haematoxylin and eosin (H&E) stain). (B) Intra‐alveolar fibrosis (H&E stain). (C) Intra‐alveolar fibrosis with azan stain. (D) Liver micro‐abscess. Scale bar: 100 μm on each image.
Discussion
Some autopsy reports of COVID‐19 patients have revealed certain clinicopathological features [3]. Autopsies could help evaluate genomic analysis results and immunochemical findings considering the pathological findings of each organ. However, performing an autopsy carries a risk of infection for pathologists and assistants. In this case, post‐mortem percutaneous needle biopsies, including pathological studies, genomic analysis, and immunochemical tests, were performed on specimens. In addition, it was possible to choose the organ from which tissue could be obtained for testing, thus reducing the risk of staff infection. Therefore, post‐mortem percutaneous needle biopsy could be an effective method to determine the cause of death in COVID‐19 patients.
In this case, genomic and immunochemical test results of the lungs and liver were negative for COVID‐19. However, PCR conducted using throat swabs or sputum showed a positive result multiple times. Among the molecular mechanisms of disease exacerbation, which contribute to cytokine storm and immune responses in COVID‐19 patients, the ACE 2 receptor‐mediated inflammatory response plays an important role [5]. In this case, the exacerbation of COVID‐19 might have been because of this mechanism rather than the direct infection of the lung by COVID‐19.
Generally, the reported median time from onset of symptoms to ARDS or admission to the intensive care unit (ICU) is 9.0–10.5 days in COVID‐19 patients [1]. In this case, the patient's COVID‐19 pneumonia was considered to have exacerbated late because his condition worsened about 25 days after the onset of symptoms with persistent positive PCR test results. There have been a few reports regarding the late exacerbation of COVID‐19 pneumonia, and the mechanism underlying it remains unknown. To date, late exacerbation of COVID‐19 was considered rare, and it was implicated that COVID‐19 patients only need a certain period (about one to two weeks) of isolation and observation. However, in this case, the patient exacerbated 25 days after the initial onset, even under proper medication and care. Therefore, more information is required for better management of exacerbated cases of COVID‐19.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Acknowledgment
We acknowledge the Department of Pathology, National Institute of Infectious Disease, Japan, for helping us perform real‐time reverse transcription PCR and immunostaining of post‐mortem percutaneous needle biopsy specimens. | CICLESONIDE, FAVIPIRAVIR, FENTANYL, METHYLPREDNISOLONE ACETATE, MIDAZOLAM, NITRIC OXIDE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM | DrugsGivenReaction | CC BY | 33664958 | 19,145,317 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Post-mortem biopsy of a patient with late exacerbation of COVID-19 pneumonia.
Pathological findings of coronavirus disease (COVID-19) have rarely been reported owing to its contagious nature. Here, we treated an 82-year-old man whose condition was diagnosed as COVID-19 pneumonia, which exacerbated approximately 25 days after the initial onset. The patient died despite receiving intensive care. Post-mortem percutaneous needle biopsy of the lungs and liver tissue was performed, including genomic analysis, immunochemical tests, and pathological studies. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage. Supposedly, the organizing phase of acute respiratory distress syndrome (ARDS) induced COVID-19. Polymerase chain reaction (PCR) test and immunostaining of biopsy specimens showed negative results for COVID-19. Post-mortem percutaneous needle biopsy was more effective in reducing the risk of contagiousness than autopsy.
Introduction
Late in December 2019, an outbreak of infections caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was reported in Wuhan, Hubei Province, China [1]. The World Health Organization named the SARS‐CoV‐2 infection as coronavirus disease (COVID‐19). COVID‐19 instantly spread worldwide, thereby becoming a pandemic. The clinical features of COVID‐19 are diverse, ranging from asymptomatic to severe pneumonia and death [2]. Genome sequencing of the virus and development of therapeutic agents and vaccines have been researched worldwide; however, pathological findings of this disease have been scarcely reported because of its contagious nature (in humans) [3]. Here, we describe pathological findings detected through post‐mortem percutaneous needle biopsy of a patient with late‐onset severe pneumonia from COVID‐19.
Case Report
The patient was an 82‐year‐old man who presented with low‐grade fever and dry cough at another hospital, where he tested positive for COVID‐19 through a polymerase chain reaction (PCR) test. He was referred to our hospital with symptoms of COVID‐19 pneumonia. He had a history of diabetes and hypertension but did not smoke. Furthermore, he had been administered a calcium channel blocker and an angiotensin‐converting enzyme (ACE) inhibitor. Chest computed tomography (CT) revealed multicentric peripheral ground‐glass opacity (GGO), especially in the right lower lobe (Fig. 1A).
Figure 1 Summary of treatment progress. Chest CT images of the patient at different stages of COVID‐19. (A) Axial view of CT from the previous hospital (day 8) shows GGO predominantly spread on the right lower lobe. (B) Axial view of CT on intubation (day 33) shows GGO spread to bilaterally and consolidation on the right lower lobe. (C) Axial view of CT on post‐mortem autopsy imaging (day 60) shows bilateral spread of consolidation and bilateral pleural effusion. AC/PC, assist control/pressure control; AC/VC, assist control/volume control; APRV, airway pressure release ventilation; COVID‐19, coronavirus disease; CT, computed tomography; GGO, ground‐glass opacity; MPEM, meropenem; MR, muscle relaxant; NC, nasal cannula; NHF, nasal high flow; NO, nitric oxide; SP, spontaneous ventilation; TAZ/PIPC, tazobactam/piperacillin; TEIC, teicoplanin.
A summary of the treatment protocol is shown in Figure 1. We administered favipiravir and ciclesonide, alongside oxygen therapy. On day 18, peripheral oxygen saturation (SpO2) and dyspnoea improved, his fever subsided, and the oxygenation therapy was withdrawn. However, the PCR tests remained positive from days 20 to 25. On day 26, SpO2 worsened, his fever returned, and oxygen therapy was resumed. Although the culture test results were negative, antibiotics (tazobactam/piperacillin, TAZ/PIPC) were administrated empirically for suspected complications of secondary infection. The patient needed intubation on day 33. CT revealed consolidation of the right lower lobe around the GGO (Fig. 1B).
The patient received mechanical ventilation in airway pressure release ventilation mode. This was in addition to nitric oxide (NO) inhalation and methylprednisolone (60 mg/day) administration to counter acute respiratory distress syndrome (ARDS). Furthermore, we administered a muscle relaxant along with fentanyl and midazolam for sedation. The patient's condition worsened on day 42, despite providing intensive care. At this stage, blood culture revealed the presence of Escherichia coli, and Stenotrophomonas maltophilia was detected in the sputum culture, suggesting ventilation‐associated pneumonia. The patient died on day 60. Autopsy CT revealed bilateral lung consolidation along with bilateral pleural effusion (Fig. 1C). There was no obvious abscess in any organ.
After obtaining informed consent from his family, we performed post‐mortem percutaneous needle biopsies of the lungs and liver tissues with a 14‐G needle. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage (DAD) (Fig. 2). In the exudative phase of DAD, the lung tissues exhibited prominent hyaline membranes with minimal chronic inflammation, while those in the organizing phase showed intra‐alveolar fibrosis. In addition, they revealed intra‐alveolar haemorrhage and reactive type II pneumocytes. Vasculitis, thrombosis, and the other pathogens were absent. There was no obvious difference between the right and left lungs. In the liver, several micro‐abscesses due to sepsis were detected. Real‐time reverse transcription PCR and immunostaining of these biopsy specimens for COVID‐19 were performed by the Department of Pathology, National Institute of Infectious Disease in Japan [4], all of which were negative. On the basis of the above‐mentioned histopathological and genomic analyses, we considered that the cause of death was ARDS due to cytokine storm, and immune responses, rather than secondary infection or other factors, induced COVID‐19.
Figure 2 Histopathology of the patient's post‐mortem percutaneous needle lung biopsy sample. (A) Diffuse alveolar damage (DAD) with hyaline membranes (→), intra‐alveolar haemorrhage, and reactive type II pneumocytes (▸) (haematoxylin and eosin (H&E) stain). (B) Intra‐alveolar fibrosis (H&E stain). (C) Intra‐alveolar fibrosis with azan stain. (D) Liver micro‐abscess. Scale bar: 100 μm on each image.
Discussion
Some autopsy reports of COVID‐19 patients have revealed certain clinicopathological features [3]. Autopsies could help evaluate genomic analysis results and immunochemical findings considering the pathological findings of each organ. However, performing an autopsy carries a risk of infection for pathologists and assistants. In this case, post‐mortem percutaneous needle biopsies, including pathological studies, genomic analysis, and immunochemical tests, were performed on specimens. In addition, it was possible to choose the organ from which tissue could be obtained for testing, thus reducing the risk of staff infection. Therefore, post‐mortem percutaneous needle biopsy could be an effective method to determine the cause of death in COVID‐19 patients.
In this case, genomic and immunochemical test results of the lungs and liver were negative for COVID‐19. However, PCR conducted using throat swabs or sputum showed a positive result multiple times. Among the molecular mechanisms of disease exacerbation, which contribute to cytokine storm and immune responses in COVID‐19 patients, the ACE 2 receptor‐mediated inflammatory response plays an important role [5]. In this case, the exacerbation of COVID‐19 might have been because of this mechanism rather than the direct infection of the lung by COVID‐19.
Generally, the reported median time from onset of symptoms to ARDS or admission to the intensive care unit (ICU) is 9.0–10.5 days in COVID‐19 patients [1]. In this case, the patient's COVID‐19 pneumonia was considered to have exacerbated late because his condition worsened about 25 days after the onset of symptoms with persistent positive PCR test results. There have been a few reports regarding the late exacerbation of COVID‐19 pneumonia, and the mechanism underlying it remains unknown. To date, late exacerbation of COVID‐19 was considered rare, and it was implicated that COVID‐19 patients only need a certain period (about one to two weeks) of isolation and observation. However, in this case, the patient exacerbated 25 days after the initial onset, even under proper medication and care. Therefore, more information is required for better management of exacerbated cases of COVID‐19.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Acknowledgment
We acknowledge the Department of Pathology, National Institute of Infectious Disease, Japan, for helping us perform real‐time reverse transcription PCR and immunostaining of post‐mortem percutaneous needle biopsy specimens. | CICLESONIDE, FAVIPIRAVIR, FENTANYL, METHYLPREDNISOLONE ACETATE, MIDAZOLAM, NITRIC OXIDE, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM | DrugsGivenReaction | CC BY | 33664958 | 19,145,317 | 2021-04 |
What was the administration route of drug 'NITRIC OXIDE'? | Post-mortem biopsy of a patient with late exacerbation of COVID-19 pneumonia.
Pathological findings of coronavirus disease (COVID-19) have rarely been reported owing to its contagious nature. Here, we treated an 82-year-old man whose condition was diagnosed as COVID-19 pneumonia, which exacerbated approximately 25 days after the initial onset. The patient died despite receiving intensive care. Post-mortem percutaneous needle biopsy of the lungs and liver tissue was performed, including genomic analysis, immunochemical tests, and pathological studies. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage. Supposedly, the organizing phase of acute respiratory distress syndrome (ARDS) induced COVID-19. Polymerase chain reaction (PCR) test and immunostaining of biopsy specimens showed negative results for COVID-19. Post-mortem percutaneous needle biopsy was more effective in reducing the risk of contagiousness than autopsy.
Introduction
Late in December 2019, an outbreak of infections caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was reported in Wuhan, Hubei Province, China [1]. The World Health Organization named the SARS‐CoV‐2 infection as coronavirus disease (COVID‐19). COVID‐19 instantly spread worldwide, thereby becoming a pandemic. The clinical features of COVID‐19 are diverse, ranging from asymptomatic to severe pneumonia and death [2]. Genome sequencing of the virus and development of therapeutic agents and vaccines have been researched worldwide; however, pathological findings of this disease have been scarcely reported because of its contagious nature (in humans) [3]. Here, we describe pathological findings detected through post‐mortem percutaneous needle biopsy of a patient with late‐onset severe pneumonia from COVID‐19.
Case Report
The patient was an 82‐year‐old man who presented with low‐grade fever and dry cough at another hospital, where he tested positive for COVID‐19 through a polymerase chain reaction (PCR) test. He was referred to our hospital with symptoms of COVID‐19 pneumonia. He had a history of diabetes and hypertension but did not smoke. Furthermore, he had been administered a calcium channel blocker and an angiotensin‐converting enzyme (ACE) inhibitor. Chest computed tomography (CT) revealed multicentric peripheral ground‐glass opacity (GGO), especially in the right lower lobe (Fig. 1A).
Figure 1 Summary of treatment progress. Chest CT images of the patient at different stages of COVID‐19. (A) Axial view of CT from the previous hospital (day 8) shows GGO predominantly spread on the right lower lobe. (B) Axial view of CT on intubation (day 33) shows GGO spread to bilaterally and consolidation on the right lower lobe. (C) Axial view of CT on post‐mortem autopsy imaging (day 60) shows bilateral spread of consolidation and bilateral pleural effusion. AC/PC, assist control/pressure control; AC/VC, assist control/volume control; APRV, airway pressure release ventilation; COVID‐19, coronavirus disease; CT, computed tomography; GGO, ground‐glass opacity; MPEM, meropenem; MR, muscle relaxant; NC, nasal cannula; NHF, nasal high flow; NO, nitric oxide; SP, spontaneous ventilation; TAZ/PIPC, tazobactam/piperacillin; TEIC, teicoplanin.
A summary of the treatment protocol is shown in Figure 1. We administered favipiravir and ciclesonide, alongside oxygen therapy. On day 18, peripheral oxygen saturation (SpO2) and dyspnoea improved, his fever subsided, and the oxygenation therapy was withdrawn. However, the PCR tests remained positive from days 20 to 25. On day 26, SpO2 worsened, his fever returned, and oxygen therapy was resumed. Although the culture test results were negative, antibiotics (tazobactam/piperacillin, TAZ/PIPC) were administrated empirically for suspected complications of secondary infection. The patient needed intubation on day 33. CT revealed consolidation of the right lower lobe around the GGO (Fig. 1B).
The patient received mechanical ventilation in airway pressure release ventilation mode. This was in addition to nitric oxide (NO) inhalation and methylprednisolone (60 mg/day) administration to counter acute respiratory distress syndrome (ARDS). Furthermore, we administered a muscle relaxant along with fentanyl and midazolam for sedation. The patient's condition worsened on day 42, despite providing intensive care. At this stage, blood culture revealed the presence of Escherichia coli, and Stenotrophomonas maltophilia was detected in the sputum culture, suggesting ventilation‐associated pneumonia. The patient died on day 60. Autopsy CT revealed bilateral lung consolidation along with bilateral pleural effusion (Fig. 1C). There was no obvious abscess in any organ.
After obtaining informed consent from his family, we performed post‐mortem percutaneous needle biopsies of the lungs and liver tissues with a 14‐G needle. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage (DAD) (Fig. 2). In the exudative phase of DAD, the lung tissues exhibited prominent hyaline membranes with minimal chronic inflammation, while those in the organizing phase showed intra‐alveolar fibrosis. In addition, they revealed intra‐alveolar haemorrhage and reactive type II pneumocytes. Vasculitis, thrombosis, and the other pathogens were absent. There was no obvious difference between the right and left lungs. In the liver, several micro‐abscesses due to sepsis were detected. Real‐time reverse transcription PCR and immunostaining of these biopsy specimens for COVID‐19 were performed by the Department of Pathology, National Institute of Infectious Disease in Japan [4], all of which were negative. On the basis of the above‐mentioned histopathological and genomic analyses, we considered that the cause of death was ARDS due to cytokine storm, and immune responses, rather than secondary infection or other factors, induced COVID‐19.
Figure 2 Histopathology of the patient's post‐mortem percutaneous needle lung biopsy sample. (A) Diffuse alveolar damage (DAD) with hyaline membranes (→), intra‐alveolar haemorrhage, and reactive type II pneumocytes (▸) (haematoxylin and eosin (H&E) stain). (B) Intra‐alveolar fibrosis (H&E stain). (C) Intra‐alveolar fibrosis with azan stain. (D) Liver micro‐abscess. Scale bar: 100 μm on each image.
Discussion
Some autopsy reports of COVID‐19 patients have revealed certain clinicopathological features [3]. Autopsies could help evaluate genomic analysis results and immunochemical findings considering the pathological findings of each organ. However, performing an autopsy carries a risk of infection for pathologists and assistants. In this case, post‐mortem percutaneous needle biopsies, including pathological studies, genomic analysis, and immunochemical tests, were performed on specimens. In addition, it was possible to choose the organ from which tissue could be obtained for testing, thus reducing the risk of staff infection. Therefore, post‐mortem percutaneous needle biopsy could be an effective method to determine the cause of death in COVID‐19 patients.
In this case, genomic and immunochemical test results of the lungs and liver were negative for COVID‐19. However, PCR conducted using throat swabs or sputum showed a positive result multiple times. Among the molecular mechanisms of disease exacerbation, which contribute to cytokine storm and immune responses in COVID‐19 patients, the ACE 2 receptor‐mediated inflammatory response plays an important role [5]. In this case, the exacerbation of COVID‐19 might have been because of this mechanism rather than the direct infection of the lung by COVID‐19.
Generally, the reported median time from onset of symptoms to ARDS or admission to the intensive care unit (ICU) is 9.0–10.5 days in COVID‐19 patients [1]. In this case, the patient's COVID‐19 pneumonia was considered to have exacerbated late because his condition worsened about 25 days after the onset of symptoms with persistent positive PCR test results. There have been a few reports regarding the late exacerbation of COVID‐19 pneumonia, and the mechanism underlying it remains unknown. To date, late exacerbation of COVID‐19 was considered rare, and it was implicated that COVID‐19 patients only need a certain period (about one to two weeks) of isolation and observation. However, in this case, the patient exacerbated 25 days after the initial onset, even under proper medication and care. Therefore, more information is required for better management of exacerbated cases of COVID‐19.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Acknowledgment
We acknowledge the Department of Pathology, National Institute of Infectious Disease, Japan, for helping us perform real‐time reverse transcription PCR and immunostaining of post‐mortem percutaneous needle biopsy specimens. | Respiratory (inhalation) | DrugAdministrationRoute | CC BY | 33664958 | 19,145,317 | 2021-04 |
What was the outcome of reaction 'Drug ineffective for unapproved indication'? | Post-mortem biopsy of a patient with late exacerbation of COVID-19 pneumonia.
Pathological findings of coronavirus disease (COVID-19) have rarely been reported owing to its contagious nature. Here, we treated an 82-year-old man whose condition was diagnosed as COVID-19 pneumonia, which exacerbated approximately 25 days after the initial onset. The patient died despite receiving intensive care. Post-mortem percutaneous needle biopsy of the lungs and liver tissue was performed, including genomic analysis, immunochemical tests, and pathological studies. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage. Supposedly, the organizing phase of acute respiratory distress syndrome (ARDS) induced COVID-19. Polymerase chain reaction (PCR) test and immunostaining of biopsy specimens showed negative results for COVID-19. Post-mortem percutaneous needle biopsy was more effective in reducing the risk of contagiousness than autopsy.
Introduction
Late in December 2019, an outbreak of infections caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was reported in Wuhan, Hubei Province, China [1]. The World Health Organization named the SARS‐CoV‐2 infection as coronavirus disease (COVID‐19). COVID‐19 instantly spread worldwide, thereby becoming a pandemic. The clinical features of COVID‐19 are diverse, ranging from asymptomatic to severe pneumonia and death [2]. Genome sequencing of the virus and development of therapeutic agents and vaccines have been researched worldwide; however, pathological findings of this disease have been scarcely reported because of its contagious nature (in humans) [3]. Here, we describe pathological findings detected through post‐mortem percutaneous needle biopsy of a patient with late‐onset severe pneumonia from COVID‐19.
Case Report
The patient was an 82‐year‐old man who presented with low‐grade fever and dry cough at another hospital, where he tested positive for COVID‐19 through a polymerase chain reaction (PCR) test. He was referred to our hospital with symptoms of COVID‐19 pneumonia. He had a history of diabetes and hypertension but did not smoke. Furthermore, he had been administered a calcium channel blocker and an angiotensin‐converting enzyme (ACE) inhibitor. Chest computed tomography (CT) revealed multicentric peripheral ground‐glass opacity (GGO), especially in the right lower lobe (Fig. 1A).
Figure 1 Summary of treatment progress. Chest CT images of the patient at different stages of COVID‐19. (A) Axial view of CT from the previous hospital (day 8) shows GGO predominantly spread on the right lower lobe. (B) Axial view of CT on intubation (day 33) shows GGO spread to bilaterally and consolidation on the right lower lobe. (C) Axial view of CT on post‐mortem autopsy imaging (day 60) shows bilateral spread of consolidation and bilateral pleural effusion. AC/PC, assist control/pressure control; AC/VC, assist control/volume control; APRV, airway pressure release ventilation; COVID‐19, coronavirus disease; CT, computed tomography; GGO, ground‐glass opacity; MPEM, meropenem; MR, muscle relaxant; NC, nasal cannula; NHF, nasal high flow; NO, nitric oxide; SP, spontaneous ventilation; TAZ/PIPC, tazobactam/piperacillin; TEIC, teicoplanin.
A summary of the treatment protocol is shown in Figure 1. We administered favipiravir and ciclesonide, alongside oxygen therapy. On day 18, peripheral oxygen saturation (SpO2) and dyspnoea improved, his fever subsided, and the oxygenation therapy was withdrawn. However, the PCR tests remained positive from days 20 to 25. On day 26, SpO2 worsened, his fever returned, and oxygen therapy was resumed. Although the culture test results were negative, antibiotics (tazobactam/piperacillin, TAZ/PIPC) were administrated empirically for suspected complications of secondary infection. The patient needed intubation on day 33. CT revealed consolidation of the right lower lobe around the GGO (Fig. 1B).
The patient received mechanical ventilation in airway pressure release ventilation mode. This was in addition to nitric oxide (NO) inhalation and methylprednisolone (60 mg/day) administration to counter acute respiratory distress syndrome (ARDS). Furthermore, we administered a muscle relaxant along with fentanyl and midazolam for sedation. The patient's condition worsened on day 42, despite providing intensive care. At this stage, blood culture revealed the presence of Escherichia coli, and Stenotrophomonas maltophilia was detected in the sputum culture, suggesting ventilation‐associated pneumonia. The patient died on day 60. Autopsy CT revealed bilateral lung consolidation along with bilateral pleural effusion (Fig. 1C). There was no obvious abscess in any organ.
After obtaining informed consent from his family, we performed post‐mortem percutaneous needle biopsies of the lungs and liver tissues with a 14‐G needle. Histopathology of the lungs showed both exudative and organizing diffuse alveolar damage (DAD) (Fig. 2). In the exudative phase of DAD, the lung tissues exhibited prominent hyaline membranes with minimal chronic inflammation, while those in the organizing phase showed intra‐alveolar fibrosis. In addition, they revealed intra‐alveolar haemorrhage and reactive type II pneumocytes. Vasculitis, thrombosis, and the other pathogens were absent. There was no obvious difference between the right and left lungs. In the liver, several micro‐abscesses due to sepsis were detected. Real‐time reverse transcription PCR and immunostaining of these biopsy specimens for COVID‐19 were performed by the Department of Pathology, National Institute of Infectious Disease in Japan [4], all of which were negative. On the basis of the above‐mentioned histopathological and genomic analyses, we considered that the cause of death was ARDS due to cytokine storm, and immune responses, rather than secondary infection or other factors, induced COVID‐19.
Figure 2 Histopathology of the patient's post‐mortem percutaneous needle lung biopsy sample. (A) Diffuse alveolar damage (DAD) with hyaline membranes (→), intra‐alveolar haemorrhage, and reactive type II pneumocytes (▸) (haematoxylin and eosin (H&E) stain). (B) Intra‐alveolar fibrosis (H&E stain). (C) Intra‐alveolar fibrosis with azan stain. (D) Liver micro‐abscess. Scale bar: 100 μm on each image.
Discussion
Some autopsy reports of COVID‐19 patients have revealed certain clinicopathological features [3]. Autopsies could help evaluate genomic analysis results and immunochemical findings considering the pathological findings of each organ. However, performing an autopsy carries a risk of infection for pathologists and assistants. In this case, post‐mortem percutaneous needle biopsies, including pathological studies, genomic analysis, and immunochemical tests, were performed on specimens. In addition, it was possible to choose the organ from which tissue could be obtained for testing, thus reducing the risk of staff infection. Therefore, post‐mortem percutaneous needle biopsy could be an effective method to determine the cause of death in COVID‐19 patients.
In this case, genomic and immunochemical test results of the lungs and liver were negative for COVID‐19. However, PCR conducted using throat swabs or sputum showed a positive result multiple times. Among the molecular mechanisms of disease exacerbation, which contribute to cytokine storm and immune responses in COVID‐19 patients, the ACE 2 receptor‐mediated inflammatory response plays an important role [5]. In this case, the exacerbation of COVID‐19 might have been because of this mechanism rather than the direct infection of the lung by COVID‐19.
Generally, the reported median time from onset of symptoms to ARDS or admission to the intensive care unit (ICU) is 9.0–10.5 days in COVID‐19 patients [1]. In this case, the patient's COVID‐19 pneumonia was considered to have exacerbated late because his condition worsened about 25 days after the onset of symptoms with persistent positive PCR test results. There have been a few reports regarding the late exacerbation of COVID‐19 pneumonia, and the mechanism underlying it remains unknown. To date, late exacerbation of COVID‐19 was considered rare, and it was implicated that COVID‐19 patients only need a certain period (about one to two weeks) of isolation and observation. However, in this case, the patient exacerbated 25 days after the initial onset, even under proper medication and care. Therefore, more information is required for better management of exacerbated cases of COVID‐19.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Acknowledgment
We acknowledge the Department of Pathology, National Institute of Infectious Disease, Japan, for helping us perform real‐time reverse transcription PCR and immunostaining of post‐mortem percutaneous needle biopsy specimens. | Fatal | ReactionOutcome | CC BY | 33664958 | 19,145,317 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Functional (Psychogenic) Movement Disorders Presenting During Sleep.
Functional (psychogenic) movement disorders are involuntary movements that seems to originate from activation of voluntary motor pathways in the brain. The movements typically present during the waking hours with variable frequency.
We present the case of a 24-year-old woman with FMDs during the waking state, but also during stages 1 and 2 of non-REM sleep and REM sleep, recorded with polysomnography. Such movements caused arousal leading to excessive daytime sleepiness and fatigue.
FMDs may disrupt sleep causing day time somnolence, adding morbidity to the disorder.
Introduction
Functional (previously known as psychogenic) movement disorders (FMDs) are involuntary movements modifiable by attention and distraction that may present with variable clinical phenomenology. Several lines of evidence suggest that FMDs originate from activation of voluntary motor pathways; however, it is unclear why they are perceived by patients as involuntary [1]. Several psychodynamic theories have been proposed to explain the pathogenesis of FMDs; however, these theories have not been able to provide a full explanation for the development of these movements and modern functional neuroimaging studies suggest that patients suffering FMDs have a distinct abnormal activation of cortical and subcortical brain structures compared to normal controls [23]. It is unclear whether this anomalous activation predispose to abnormal movements or results from them. Moreover, it is uncertain whether such abnormal brain activation may present, in some cases, during states of decreased physiological consciousness such as sleep, leading to the appearance of FMDs. Here, we report a patient with documented FMDs during sleep and discuss possible underlying pathogenesis.
Case Report
A 24-year-old, right handed, Hispanic woman, presented for evaluation of a 6-month history of episodic axial and appendicular dystonia, causing severe opisthotonus and twisted postures in the upper and lower limbs of variable duration lasting from few seconds to 3–4 hours, the episodes were sometimes preceded by stereotypic finger movements and sometimes accompanied by hand tremor and severe stuttering. These episodes started suddenly after a minor car accident and presented several times a day. The presence of marked suggestibility, distractibility, prominent stuttering associated with the dystonic episodes [4]; sudden onset of abnormal movements with periods of unexplained improvement; lack of family history of dystonia and normal brain magnetic resonance imaging were consistent with FMDs. No abnormalities in cranial nerves, muscle strength, deep tendon reflexes, sensation and gait were documented in this patient. She underwent a video-EEG (VEEG) examination awake (6 h) showing multiple spells of abnormal dystonic movements with lack of electroencephalographic correlation.
The patient’s parents noted similar dystonic movements while the patient was sleeping almost every night. They denied similar movements during sleep before the onset of FMDs. There was no personal or family history of parasomnias such as sleepwalking, night terrors, or confusional arousals. The patient complained of fragmented sleep, as the movements wake her up 2 to 3 times per night causing fatigue and excessive daytime sleepiness. She scored 20 out of 24 points in the Epworth Sleepiness Scale (ESS). There were no complains of snoring, nocturia or myoclonic movements during the sleep time. The patient denied drinking coffee, tea or soft drinks before going to sleep. Sleep habits included a consistent bedtime at 11:30 p.m. and awakening at 7.30 a.m., daily naps of 2 hours during the afternoon were also endorsed by the patient.
The patient underwent 2 overnight polysomnographs (PSG) (Alice 5 type 1, Respironics Inc., Murrysville, Penn. USA), according to the guidelines of the American Academy of Sleep Medicine (www.aasmnet.org). In the first PSG study, there was a delayed rapid eye movement (REM) sleep, with a latency of 248 minutes; there were 2 episodes of mild distal upper and lower limb spasms during non-REM sleep stage 2, lasting 37 and 40.5 seconds respectively (Figure 1), the first episode was related to awakening, in the second episode the patient remained in stage 1; a third episode with similar features presented during non-REM sleep stage 1 lasting 18 seconds. The patient remained in stage 1 after the movements subsided. A fourth episode of upper limb and axial dystonia lasting 30 seconds was observed during REM sleep, followed by awakening (Figure 1). There were no other sleep-related breathing or movement disorders (Table 1). In a second PSG carried out two weeks later, two episodes of mild distal dystonic movements presented during non-REM sleep stage 1 followed by arousal and severe generalized dystonia (see video). All episodes observed during PSG were clinically similar to those observed during video-EEG and none of them was related to electroencephalographic evidence of epileptic activity.
Figure 1 A) Hypnogram for PSG-1 showing the occurrence of dystonic episodes (arrows). NREM: E1: stage 1, E2: stage 2, E3: stage 3, R: REM; W: awake. B) Episode of dystonia which translates into EMG activity, occurring during the NREM-E2; EEG shows multiple sleep spindles and K complexes consistent with this phase of sleep; picture shows axial and upper limb dystonia registered in the EMG.
Table 1 Summary of sleep parameters during the PSG-1.
TIME AND NUMBER
Total sleep time (TST= REM+NREM) 399 min
Sleep efficiency: Time asleep/(total time in bed-time to fall sleep) 87.7%
Total number of arousals 95
Arousal index 14.3/h
Distribution of sleep stages
Awake 56 min
NREM Total 357 min
E1 57 min
E2 231 min
E3 69 min
E4 0 min
REM 42 min
Sleep latencies
E1 37.5 min
REM 248 min
Periodic limb movement during sleep 0
Total number of lower limb movements 24
Snoring
Total number of snoring episodes 9
Mean duration of snoring episodes 3.4 sec
Total time snoring 0.5 min
Apnea/hypopnea Index (Apnea:hypopnea/TST)
NREM 0.2/h
REM 0.0/h
TST 0.2/h
REM: rapid-eye movements; non-REM sleep stages: E1: stage 1, E2: stage 2, E3: stage 3, E4: stage 4. TST: total sleep times.
Video Patient shows hand stereotypes and dystonia followed by axial dystonia with opisthotonus during early phases of non-REM sleep. These episodes were registered by EMG as shown in figure 1B.
An initial trial of high doses of antiepileptic drugs was provided elsewhere including levetiracetam 1500 mg twice a day, phenytoin 100 mg three times a day and valproate 600 mg three times a day for two weeks each, without any benefit and they were discontinued. At the initial evaluation by us, the patient was receiving treatment with escitalopram oxalate 20 mg per day without any benefit in her abnormal movements.
However, treatment with physiotherapy, psychotherapy plus alprazolam 1 mg per night then substituted by clonazepam up-to 4 mg per night and mirtazapine from 7.5 to 22.5 mg per night, provided marked improvement with disappearance of sleep fragmentation, dystonic movements during sleep and excessive daytime sleepiness within the first 3 months after starting multidisciplinary treatment, whereas movements awake had a slower but progressive improvement within the next 10 months. The patient has been without mirtazapine and benzodiazepines within the last 5 to 6 months without recurrence of sleep and awake movements.
Discussion
We report a patient fulfilling diagnostic criteria for “documented” and “clinically established” FMDs according to the Fahn and Williams criteria [5]. She showed similar dystonic movements during early phases of non-REM sleep and REM-sleep, disrupting her sleep cycles leading to daytime sleepiness and fatigue. After extensive investigations with VEEG and PSG, there was no evidence of some forms of epilepsy including frontal lobe epilepsy which it may present with seizures during sleep. The spells during sleep improved without anti-epileptics, and improvement persisted after discontinuing benzodiazepines and mirtazapine. Moreover, there was no evidence either of epileptic seizures while awake. Some paroxysmal movement disorders such as those related to MR1, KCNMA1 and ATP1A3 mutations may improve with benzodiazepines; however, these disorders show a much younger age at onset (around 5 years), have clear precipitants, do not seem to present during sleep and they should recur following discontinuation of benzodiazepines.
A number of sleep-related movement disorders have been recognized according to the International Classification of Sleep Disorders third edition (ICSD3) [6], including: restless legs syndrome, sleep-related leg cramps, sleep bruxism, sleep-related leg cramps, benign sleep myoclonus of infancy, periodic limb movement disorder, sleep-related rhythmic movement disorders, and propriospinal myoclonus (PSM); however, the majority of these movements have a myoclonic character and a rhythmic or periodical presentation instead of the dystonic and non—rhythmic pattern registered in our patient [7]. The ICSD3 also categorizes “sleep-related movement disorders” as “unspecified”, they may be due to medication or medical disorder; we consider that our patient fits into the latter category. Trauma associated sleep disorder (TASD) is a recently described condition characterized by: previous traumatic experience, nightmares related to the traumatic event, dream enactment behaviors during REM and non-REM sleep, autonomic hyperarousal and lack of epileptic activity on EEG [89]. Some of these features were observed in our patient with the notable lack of nightmares related to the traumatic event, whether our patient’s manifestations are a subtype of TASD or a different disorder is uncertain.
PSM is a movement disorder occurring during the sleep-wake transition [10]. Although PSM was considered a variant of organic axial myoclonus, a substantial proportion of patients with PSM are believed to have a functional neurological disorder, based on the observation that the movements can be imitated voluntarily and the presence of Bereitschaftspotential preceding PSM [11]. For this reason, PSM may be an example of a FMD presenting in the sleep-wake transition that can potentially disrupt sleep.
On the other hand, sleep-related bruxism consists in rhythmic contractions of the masticatory muscles leading to tooth grinding, typically occur in light non-REM sleep and during REM sleep [7]; evidence suggests that these episodes are related to micro-arousal [12]. Both features were also observed in our patient, but with movements similar to those experienced while awake during an attack of functional dystonia and stereotypies. Interestingly, our patient had dystonic movements during REM sleep with lack of atonia, we were not able to confirm dream enactment; however, these features suggest the presence REM sleep behavior disorder (RBD); although this disorder frequently heralds the onset of a neurodegenerative disorders, it may occur associated with certain medications such as selective serotonin reuptake inhibitors (SSRIs), or neurological disorders including narcolepsy, Tourette syndrome (TS) [6] and possibly FMDs as demonstrated by this case.
Movements during sleep, similar to those observed during awakening in patients with FMDs may be related to a state of hyperarousal and decreased intracortical inhibition involving motor pathways; both abnormalities have been documented in patients with FMDs [1314]; and have also been proposed to explain the increased motor activity and tics during REM and non-REM sleep observed in patients with TS [15]. Current evidence suggests that patients with FMDs may have abnormally enhanced connections between limbic/emotional and motor systems [16]; making the latter more prone to activate under certain external or internal stimuli; this activation may possibly occur during different sleep stages or during the sleep-wake transition.
In our patient, improvement was observed following a multidisciplinary therapy with dystonic movements during sleep disappearing before FMDs while awake. Suggesting that movements during sleep are more susceptible to disappear with appropriate treatment; however, deepening of sleep induced by benzodiazepines may have also contributed to such improvement.
In conclusion, abnormal movements disrupting sleep or sleep-awake transition causing daytime sleepiness may be present in some patients with FMDs. Besides their impact in sleep quality, they may lead to microarousals, daytime sleepiness and fatigue [17]. The presence of such movements during sleep, challenges the notion that these movements would only present during the waking state. The patient also showed dystonic movements during REM sleep, suggesting the presence of RBD, possibly expanding the list of disorders related to this parasomnia and overlapping with TASD. Further studies should help to determine how frequently these phenomena occur during sleep and their clinical correlations in patients with FMDs. We are not aware of previous reports of FMDs during sleep; we encourage clinicians and researchers to look for signs of disrupted sleep and document abnormal movements during sleep in these patients.
Data Accessibility Statements
Data is available on request to the authors.
Acknowledgement
To Dr. Claudia Laguna for her assistance in the review and interpretation of polysomnographs.
Abbreviations
EEG: electroencephalogram
FMDs: Functional movement disorders
ESS: Epworth Sleepiness Scale
PSM: propriospinal myoclonus
REM: rapid eye movement
PSG: polysomnographs
Ethics and Consent
The authors confirm that the approval of an institutional review board was not required for this work. The patient provided written informed consent to participate in the study.
Written informed consent to publish this information was obtained from the study participant
Competing Interests
The authors have no competing interests to declare.
Author contributions
All authors read and approved the manuscript. JFBC: 1A, 1B, 1C, 3A, 3B. MAJ: 1B, 1C, 3A. RF: 1B, 3B
Research project: A. Conception, B. Organization, C. Execution;
Statistical Analysis: A. Design, B. Execution, C. Review and Critique;
Manuscript: A. Writing of the first draft, B. Review and Critique. | ESCITALOPRAM OXALATE, LEVETIRACETAM, PHENYTOIN SODIUM, VALPROIC ACID | DrugsGivenReaction | CC BY | 33664989 | 19,381,576 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Functional (Psychogenic) Movement Disorders Presenting During Sleep.
Functional (psychogenic) movement disorders are involuntary movements that seems to originate from activation of voluntary motor pathways in the brain. The movements typically present during the waking hours with variable frequency.
We present the case of a 24-year-old woman with FMDs during the waking state, but also during stages 1 and 2 of non-REM sleep and REM sleep, recorded with polysomnography. Such movements caused arousal leading to excessive daytime sleepiness and fatigue.
FMDs may disrupt sleep causing day time somnolence, adding morbidity to the disorder.
Introduction
Functional (previously known as psychogenic) movement disorders (FMDs) are involuntary movements modifiable by attention and distraction that may present with variable clinical phenomenology. Several lines of evidence suggest that FMDs originate from activation of voluntary motor pathways; however, it is unclear why they are perceived by patients as involuntary [1]. Several psychodynamic theories have been proposed to explain the pathogenesis of FMDs; however, these theories have not been able to provide a full explanation for the development of these movements and modern functional neuroimaging studies suggest that patients suffering FMDs have a distinct abnormal activation of cortical and subcortical brain structures compared to normal controls [23]. It is unclear whether this anomalous activation predispose to abnormal movements or results from them. Moreover, it is uncertain whether such abnormal brain activation may present, in some cases, during states of decreased physiological consciousness such as sleep, leading to the appearance of FMDs. Here, we report a patient with documented FMDs during sleep and discuss possible underlying pathogenesis.
Case Report
A 24-year-old, right handed, Hispanic woman, presented for evaluation of a 6-month history of episodic axial and appendicular dystonia, causing severe opisthotonus and twisted postures in the upper and lower limbs of variable duration lasting from few seconds to 3–4 hours, the episodes were sometimes preceded by stereotypic finger movements and sometimes accompanied by hand tremor and severe stuttering. These episodes started suddenly after a minor car accident and presented several times a day. The presence of marked suggestibility, distractibility, prominent stuttering associated with the dystonic episodes [4]; sudden onset of abnormal movements with periods of unexplained improvement; lack of family history of dystonia and normal brain magnetic resonance imaging were consistent with FMDs. No abnormalities in cranial nerves, muscle strength, deep tendon reflexes, sensation and gait were documented in this patient. She underwent a video-EEG (VEEG) examination awake (6 h) showing multiple spells of abnormal dystonic movements with lack of electroencephalographic correlation.
The patient’s parents noted similar dystonic movements while the patient was sleeping almost every night. They denied similar movements during sleep before the onset of FMDs. There was no personal or family history of parasomnias such as sleepwalking, night terrors, or confusional arousals. The patient complained of fragmented sleep, as the movements wake her up 2 to 3 times per night causing fatigue and excessive daytime sleepiness. She scored 20 out of 24 points in the Epworth Sleepiness Scale (ESS). There were no complains of snoring, nocturia or myoclonic movements during the sleep time. The patient denied drinking coffee, tea or soft drinks before going to sleep. Sleep habits included a consistent bedtime at 11:30 p.m. and awakening at 7.30 a.m., daily naps of 2 hours during the afternoon were also endorsed by the patient.
The patient underwent 2 overnight polysomnographs (PSG) (Alice 5 type 1, Respironics Inc., Murrysville, Penn. USA), according to the guidelines of the American Academy of Sleep Medicine (www.aasmnet.org). In the first PSG study, there was a delayed rapid eye movement (REM) sleep, with a latency of 248 minutes; there were 2 episodes of mild distal upper and lower limb spasms during non-REM sleep stage 2, lasting 37 and 40.5 seconds respectively (Figure 1), the first episode was related to awakening, in the second episode the patient remained in stage 1; a third episode with similar features presented during non-REM sleep stage 1 lasting 18 seconds. The patient remained in stage 1 after the movements subsided. A fourth episode of upper limb and axial dystonia lasting 30 seconds was observed during REM sleep, followed by awakening (Figure 1). There were no other sleep-related breathing or movement disorders (Table 1). In a second PSG carried out two weeks later, two episodes of mild distal dystonic movements presented during non-REM sleep stage 1 followed by arousal and severe generalized dystonia (see video). All episodes observed during PSG were clinically similar to those observed during video-EEG and none of them was related to electroencephalographic evidence of epileptic activity.
Figure 1 A) Hypnogram for PSG-1 showing the occurrence of dystonic episodes (arrows). NREM: E1: stage 1, E2: stage 2, E3: stage 3, R: REM; W: awake. B) Episode of dystonia which translates into EMG activity, occurring during the NREM-E2; EEG shows multiple sleep spindles and K complexes consistent with this phase of sleep; picture shows axial and upper limb dystonia registered in the EMG.
Table 1 Summary of sleep parameters during the PSG-1.
TIME AND NUMBER
Total sleep time (TST= REM+NREM) 399 min
Sleep efficiency: Time asleep/(total time in bed-time to fall sleep) 87.7%
Total number of arousals 95
Arousal index 14.3/h
Distribution of sleep stages
Awake 56 min
NREM Total 357 min
E1 57 min
E2 231 min
E3 69 min
E4 0 min
REM 42 min
Sleep latencies
E1 37.5 min
REM 248 min
Periodic limb movement during sleep 0
Total number of lower limb movements 24
Snoring
Total number of snoring episodes 9
Mean duration of snoring episodes 3.4 sec
Total time snoring 0.5 min
Apnea/hypopnea Index (Apnea:hypopnea/TST)
NREM 0.2/h
REM 0.0/h
TST 0.2/h
REM: rapid-eye movements; non-REM sleep stages: E1: stage 1, E2: stage 2, E3: stage 3, E4: stage 4. TST: total sleep times.
Video Patient shows hand stereotypes and dystonia followed by axial dystonia with opisthotonus during early phases of non-REM sleep. These episodes were registered by EMG as shown in figure 1B.
An initial trial of high doses of antiepileptic drugs was provided elsewhere including levetiracetam 1500 mg twice a day, phenytoin 100 mg three times a day and valproate 600 mg three times a day for two weeks each, without any benefit and they were discontinued. At the initial evaluation by us, the patient was receiving treatment with escitalopram oxalate 20 mg per day without any benefit in her abnormal movements.
However, treatment with physiotherapy, psychotherapy plus alprazolam 1 mg per night then substituted by clonazepam up-to 4 mg per night and mirtazapine from 7.5 to 22.5 mg per night, provided marked improvement with disappearance of sleep fragmentation, dystonic movements during sleep and excessive daytime sleepiness within the first 3 months after starting multidisciplinary treatment, whereas movements awake had a slower but progressive improvement within the next 10 months. The patient has been without mirtazapine and benzodiazepines within the last 5 to 6 months without recurrence of sleep and awake movements.
Discussion
We report a patient fulfilling diagnostic criteria for “documented” and “clinically established” FMDs according to the Fahn and Williams criteria [5]. She showed similar dystonic movements during early phases of non-REM sleep and REM-sleep, disrupting her sleep cycles leading to daytime sleepiness and fatigue. After extensive investigations with VEEG and PSG, there was no evidence of some forms of epilepsy including frontal lobe epilepsy which it may present with seizures during sleep. The spells during sleep improved without anti-epileptics, and improvement persisted after discontinuing benzodiazepines and mirtazapine. Moreover, there was no evidence either of epileptic seizures while awake. Some paroxysmal movement disorders such as those related to MR1, KCNMA1 and ATP1A3 mutations may improve with benzodiazepines; however, these disorders show a much younger age at onset (around 5 years), have clear precipitants, do not seem to present during sleep and they should recur following discontinuation of benzodiazepines.
A number of sleep-related movement disorders have been recognized according to the International Classification of Sleep Disorders third edition (ICSD3) [6], including: restless legs syndrome, sleep-related leg cramps, sleep bruxism, sleep-related leg cramps, benign sleep myoclonus of infancy, periodic limb movement disorder, sleep-related rhythmic movement disorders, and propriospinal myoclonus (PSM); however, the majority of these movements have a myoclonic character and a rhythmic or periodical presentation instead of the dystonic and non—rhythmic pattern registered in our patient [7]. The ICSD3 also categorizes “sleep-related movement disorders” as “unspecified”, they may be due to medication or medical disorder; we consider that our patient fits into the latter category. Trauma associated sleep disorder (TASD) is a recently described condition characterized by: previous traumatic experience, nightmares related to the traumatic event, dream enactment behaviors during REM and non-REM sleep, autonomic hyperarousal and lack of epileptic activity on EEG [89]. Some of these features were observed in our patient with the notable lack of nightmares related to the traumatic event, whether our patient’s manifestations are a subtype of TASD or a different disorder is uncertain.
PSM is a movement disorder occurring during the sleep-wake transition [10]. Although PSM was considered a variant of organic axial myoclonus, a substantial proportion of patients with PSM are believed to have a functional neurological disorder, based on the observation that the movements can be imitated voluntarily and the presence of Bereitschaftspotential preceding PSM [11]. For this reason, PSM may be an example of a FMD presenting in the sleep-wake transition that can potentially disrupt sleep.
On the other hand, sleep-related bruxism consists in rhythmic contractions of the masticatory muscles leading to tooth grinding, typically occur in light non-REM sleep and during REM sleep [7]; evidence suggests that these episodes are related to micro-arousal [12]. Both features were also observed in our patient, but with movements similar to those experienced while awake during an attack of functional dystonia and stereotypies. Interestingly, our patient had dystonic movements during REM sleep with lack of atonia, we were not able to confirm dream enactment; however, these features suggest the presence REM sleep behavior disorder (RBD); although this disorder frequently heralds the onset of a neurodegenerative disorders, it may occur associated with certain medications such as selective serotonin reuptake inhibitors (SSRIs), or neurological disorders including narcolepsy, Tourette syndrome (TS) [6] and possibly FMDs as demonstrated by this case.
Movements during sleep, similar to those observed during awakening in patients with FMDs may be related to a state of hyperarousal and decreased intracortical inhibition involving motor pathways; both abnormalities have been documented in patients with FMDs [1314]; and have also been proposed to explain the increased motor activity and tics during REM and non-REM sleep observed in patients with TS [15]. Current evidence suggests that patients with FMDs may have abnormally enhanced connections between limbic/emotional and motor systems [16]; making the latter more prone to activate under certain external or internal stimuli; this activation may possibly occur during different sleep stages or during the sleep-wake transition.
In our patient, improvement was observed following a multidisciplinary therapy with dystonic movements during sleep disappearing before FMDs while awake. Suggesting that movements during sleep are more susceptible to disappear with appropriate treatment; however, deepening of sleep induced by benzodiazepines may have also contributed to such improvement.
In conclusion, abnormal movements disrupting sleep or sleep-awake transition causing daytime sleepiness may be present in some patients with FMDs. Besides their impact in sleep quality, they may lead to microarousals, daytime sleepiness and fatigue [17]. The presence of such movements during sleep, challenges the notion that these movements would only present during the waking state. The patient also showed dystonic movements during REM sleep, suggesting the presence of RBD, possibly expanding the list of disorders related to this parasomnia and overlapping with TASD. Further studies should help to determine how frequently these phenomena occur during sleep and their clinical correlations in patients with FMDs. We are not aware of previous reports of FMDs during sleep; we encourage clinicians and researchers to look for signs of disrupted sleep and document abnormal movements during sleep in these patients.
Data Accessibility Statements
Data is available on request to the authors.
Acknowledgement
To Dr. Claudia Laguna for her assistance in the review and interpretation of polysomnographs.
Abbreviations
EEG: electroencephalogram
FMDs: Functional movement disorders
ESS: Epworth Sleepiness Scale
PSM: propriospinal myoclonus
REM: rapid eye movement
PSG: polysomnographs
Ethics and Consent
The authors confirm that the approval of an institutional review board was not required for this work. The patient provided written informed consent to participate in the study.
Written informed consent to publish this information was obtained from the study participant
Competing Interests
The authors have no competing interests to declare.
Author contributions
All authors read and approved the manuscript. JFBC: 1A, 1B, 1C, 3A, 3B. MAJ: 1B, 1C, 3A. RF: 1B, 3B
Research project: A. Conception, B. Organization, C. Execution;
Statistical Analysis: A. Design, B. Execution, C. Review and Critique;
Manuscript: A. Writing of the first draft, B. Review and Critique. | ESCITALOPRAM OXALATE, LEVETIRACETAM, PHENYTOIN SODIUM, VALPROIC ACID | DrugsGivenReaction | CC BY | 33664989 | 19,381,576 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaphylactic reaction'. | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | CEFAZOLIN, DEXAMETHASONE, FENTANYL, LIDOCAINE, MIDAZOLAM, PROPOFOL, SUCCINYLCHOLINE, VITAMINS | DrugsGivenReaction | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood pressure immeasurable'. | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | CEFAZOLIN, DEXAMETHASONE, FENTANYL, LIDOCAINE, MIDAZOLAM, PROPOFOL, SUCCINYLCHOLINE, VITAMINS | DrugsGivenReaction | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotension'. | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | CEFAZOLIN, DEXAMETHASONE, FENTANYL, LIDOCAINE, MIDAZOLAM, PROPOFOL, SUCCINYLCHOLINE, VITAMINS | DrugsGivenReaction | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'. | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | CEFAZOLIN, DEXAMETHASONE, FENTANYL, LIDOCAINE, MIDAZOLAM, PROPOFOL, SUCCINYLCHOLINE, VITAMINS | DrugsGivenReaction | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary arterial hypertension'. | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | CEFAZOLIN, DEXAMETHASONE, FENTANYL, LIDOCAINE, MIDAZOLAM, PROPOFOL, SUCCINYLCHOLINE, VITAMINS | DrugsGivenReaction | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sinus tachycardia'. | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | CEFAZOLIN, DEXAMETHASONE, FENTANYL, LIDOCAINE, MIDAZOLAM, PROPOFOL, SUCCINYLCHOLINE, VITAMINS | DrugsGivenReaction | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the administration route of drug 'CEFAZOLIN'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the administration route of drug 'DEXAMETHASONE'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the administration route of drug 'FENTANYL'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the administration route of drug 'LIDOCAINE'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the administration route of drug 'MIDAZOLAM'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the administration route of drug 'PROPOFOL'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the administration route of drug 'SUCCINYLCHOLINE'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the dosage of drug 'VITAMINS'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | UNK, QD | DrugDosageText | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the outcome of reaction 'Anaphylactic reaction'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Recovered | ReactionOutcome | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the outcome of reaction 'Blood pressure immeasurable'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Recovered | ReactionOutcome | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the outcome of reaction 'Hypotension'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Recovered | ReactionOutcome | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the outcome of reaction 'Metabolic acidosis'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Recovered | ReactionOutcome | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the outcome of reaction 'Pulmonary arterial hypertension'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Recovered | ReactionOutcome | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
What was the outcome of reaction 'Sinus tachycardia'? | Intraoperative Hypotension in a Patient with Antithrombin Deficiency, Bilateral Pulmonary Emboli, and Cefazolin Allergy.
In medicine, the search for a clear answer can at times be elusive. However, this does not necessarily preclude the administration of intelligent and thoughtful therapeutic treatments. Here, we describe a complicated emergent event of severe hypotension and near-arrest that occurred in the operating room in a young, healthy woman undergoing outpatient thyroid surgery. We detail the situation as it presented in the operating room and the measures taken to rule out potential life-threatening diagnoses and develop a thoughtful treatment plan. We further describe the evidence for and against the two remaining diagnostic possibilities: anaphylaxis versus acute pulmonary embolism.
Introduction
Emergent situations are inherent to the profession of anesthesiology. The case report described here involves a patient who had occult antithrombin (AT) deficiency, diagnosed in the aftermath of an emergent near-arrest that occurred after anesthesia induction and prior to surgical incision in a healthy young woman presenting for outpatient resection of a thyroid neoplasm. We describe the clinical features encountered and steps taken during this complicated emergent event, which exhibited signs of both acute pulmonary embolus (PE) and anaphylaxis. We further discuss the differential diagnosis and how diagnoses were quickly ruled out to best optimize treatment.
AT is an endogenous anticoagulant produced by the liver that inhibits activated clotting factors in plasma, most notably thrombin (factor IIa) and factor Xa. AT causes less significant inhibition of factors IXa, XIa, and XIIa. AT also inhibits several serine proteases such as plasmin, kallikrein, urokinase, and tissue plasminogen activator [1].
AT deficiency has a reported prevalence of one in 500 to one in 5,000 in the overall population. It is transmitted genetically in an autosomal dominant manner, and patients living with the disease tend to be heterozygotes, as the extremely rare cases of homozygous AT deficiency result in death in utero [1]. Due to the deficiency, patients typically present in a hypercoagulable state with recurrent venous thromboses that incur elevated mortality risk secondary to pulmonary emboli [1-2].
Two different types of AT deficiencies exist in the patient population. Type I AT deficiency (12% of AT-deficient patients) results in decreased quantity and function of antithrombin and type II AT deficiency (88%) results in normal quantity and abnormal function. Type II AT deficiency is further subdivided into three different forms: IIa in which the defect is in the thrombin binding domain, IIb in which the defect is in the heparin-binding domain, and IIc, the mixed or pleiotropic form [1].
Perioperative anaphylaxis occurs at an estimated frequency of one in 1,250 to one in 18,600 cases [3]. This acute event can pose a true life-threatening emergency, and mortality is estimated at 3% to 9% [4]. Early detection and treatment are key to patient survival and prevention of associated complications [5- 6]. While any perioperative medication or material can pose an anaphylactic risk, the most common reactions are to the neuromuscular blocking agents, antibiotics, disinfectants, and latex [6].
Case presentation
A 36-year-old female with a past medical history of prediabetes and mildly elevated body mass index (BMI) of 28 kg/m2 presented to the outpatient surgery center for resection of a right thyroid nodule consistent with follicular neoplasm (Hurthle Cell Type, Bethesda IV) with NRAS and copy number alterations. She had no known medication allergies and no significant history of smoking, alcohol, or drug use. She was not taking any home medications, only a daily multivitamin. Family history revealed a brother with a prior transient ischemic attack and coronary artery disease in both her father and brother.
The patient was given 2 mg of intravenous (IV) midazolam and taken to the operating room (OR) for induction of anesthesia. After a standard World Health Organization (WHO) timeout, anesthesia was induced at 9:13 am with 150 mg of IV propofol preceded one minute prior by 50 mcg of IV fentanyl and 60 mg of IV lidocaine. After induction, she received 100 mg of IV succinylcholine for muscle paralysis prior to intubation, which was uneventful. At 9:15 am, she received 10 mg IV dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. The next medication administered was 2 gm of IV cefazolin at 9:20 am.
At this time the patient’s pulse rate was modestly increased at 108 beats per minute (bpm) compared with her baseline of 71 bpm. Pulse oximetry (SpO2) measured 100% on a fraction of inspired oxygen (FiO2) of 67%. Her blood pressure was stable and end-tidal carbon dioxide (EtCO2) measured 34 cmH2O. By 9:23 am, three minutes later, she developed sinus tachycardia in the 120s, which increased to the 140s by 9:25 am despite an additional dose of 50 mcg of IV fentanyl and 10 mg of IV esmolol. Blood pressure was still stable with a mean arterial pressure (MAP) of 101 mmHg. Within five minutes, the EtCO2 decreased precipitously to 16 cmH2O, whereupon the noninvasive blood pressure readings became unmeasurable. Tachycardia persisted, and the patient suffered from severe hypotension despite multiple boluses of phenylephrine (0.1 mg), epinephrine (0.1 mg, 0.4 mg, and 0.5 mg), and vasopressin (2 units to 5 units). The patient had clear lungs on auscultation and no significant increase in peak inspiratory pressures as measured by the ventilator. A violaceous mottling was noted in the hands and on the chest.
The operation was canceled, and a rapid response team alert implemented to enlist additional support. The FiO2 was increased to 100%, and the volatile anesthetic vaporizer turned off. The surgeon came to the head of the operating table to manually palpate a carotid pulse, which was maintained despite the inability of the automated cuff to detect blood pressure. Palpation of the carotid pulse continued until the anesthesia team successfully placed a brachial arterial line via ultrasound. A femoral central line was placed emergently by the surgical team. The patient’s vital signs finally stabilized on a titrated epinephrine infusion. An arterial blood gas revealed acute metabolic acidosis; the patient received two ampoules of 8.4% sodium bicarbonate and an ampoule of 10% calcium chloride. Diphenhydramine and famotidine were given presumptively for anaphylaxis, though the differential also included acute PE given her history of malignancy.
A serum tryptase sent several hours after the initial critical event was found to be elevated at 14.4 ug/L. The following day, a computed tomography angiogram (CTA) of the chest revealed subtle small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery. Small peripheral pulmonary arterial filling defects were noted in the right upper and left lower lobes consistent with small pulmonary emboli and enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension (Figure 1).
Figure 1 CTA of the chest performed on POD 1 revealed subtle, small peripheral pulmonary arterial filling defects noted in the right upper and left lower lobes consistent with small pulmonary emboli. Enlargement of the main pulmonary artery, which may be seen in the setting of pulmonary arterial hypertension.
CTA, computed tomography angiogram; POD, postoperative day
Lower extremity Doppler imaging followed, revealing a mild eccentric nonocclusive right common femoral vein thrombus that appeared chronic (Figures 2-3).
Figure 2 US of the lower extremities revealed a chronic DVT in the right common femoral vein as indicated between the hash marks
US, ultrasound; DVT, deep venous thrombosis
Figure 3 Doppler color flow demonstrated the right common femoral DVT was nonocclusive.
DVT, deep venous thrombosis
Doppler of the right upper extremity revealed an incidental finding of an occlusive thrombus in the distal basilic vein. The patient was started on full-dose enoxaparin (80 mg, subcutaneous, every 12 hours) and a later workup for inherited coagulopathies ensued. The patient was found to have decreased AT activity measuring 65% (normal range: 76-128%) and decreased AT antigen of 54% (normal range: 82-136%). These two features are indicative of type I AT deficiency [1]. Further imaging suggested that ovarian masses resulting in venous compression could have contributed to the chronic deep venous thrombosis (DVT) and subsequent PE (Figure 4).
Figure 4 Coronal MR image of the pelvis showing bilateral adnexal cystic masses
MR, magnetic resonance
The patient was extubated on postoperative day (POD) 1 and discharged home on POD 3. A transesophageal echocardiogram was not performed. After discharge, she had a follow-up with both hematology and allergy/immunology. At her hematology appointment, she was transitioned from enoxaparin to apixaban, which she will remain on indefinitely with enoxaparin bridging, as needed, for surgical procedures. Testing by her allergist revealed a high degree of reactivity to cefazolin, who suggested this as the possible cause of her near-arrest but noted: “it is also possible that another medication or medical event was responsible for the reaction in the OR and not due to cefazolin.” Of note, the patient was started on empiric antibiotics the first day into her ICU course postoperatively because of elevated lactic acid. At that time, she received two doses of ceftriaxone, another cephalosporin, for treatment without incident. She has had several surgeries since, in which she received the same anesthetic agents and medications including midazolam, fentanyl, lidocaine, propofol, succinylcholine, and dexamethasone, all without incident.
Discussion
This case, in which an unexpected near-arrest occurred intraoperatively, demonstrates the importance of maintaining vigilance during anesthetic administration in the operating room, focusing not only on the vitals and monitors but also on the patient who is often obscured or partially accessible due to surgical drapes. The key event noted here, which heralded the subsequent differential diagnosis, was a constellation of changes in the patient’s vital signs and physical exam noticed by the anesthesiologist. These included a sudden drop in end-tidal CO2 and O2 saturation, accompanied by severe hypotension and tachycardia.
According to the Stanford Emergency Manual, there are several life-threatening conditions that can present intraoperatively in this manner, including PE, anaphylaxis, myocardial infarction (MI), pneumothorax, anesthetic overdose, hemorrhage, and aspiration [7]. In this case, these diagnoses were considered and ruled out until only two realistic possibilities remained: pulmonary embolism versus anaphylaxis. An MI was extremely unlikely in a young healthy woman with no significant cardiac risk factors. Pneumothorax was unlikely given the absence of increased peak airway pressures on the ventilator nor a precipitating event to cause such a complication. The patient had typical doses of anesthetic for her age and weight and was at less than one minimum alveolar concentration (MAC) of sevoflurane anesthesia, an end-tidal concentration of 1.69%, when the event occurred, thus ruling out anesthetic overdose. A hemorrhage was ruled out by the timing since surgery had not commenced. And aspiration was unlikely given that the patient was appropriately nil per os (NPO) for her elective surgery with no risk factors such as gastroesophageal reflux (GERD) or gastroparesis, nor was any evidence of aspiration witnessed during intubation.
There was compelling evidence to support the diagnosis of both pulmonary embolism and anaphylaxis in this rapidly evolving emergent situation. Acute pulmonary emboli are known to cause a sudden increase in dead space and a concurrent drop in EtCO2 with hypoxia and tachycardia [8]. Violaceous mottling was noted in the fingertips, which is more likely to be seen in acute pulmonary embolism versus anaphylaxis where vasodilation and hyper-perfusion occur. A diagnosis of anaphylaxis was possible given the timing of the event, just shortly after anesthetic induction and antibiotic administration, in which a host of medications were given in a short period of time [6]. Of note, there were no increased peak airway pressures or evidence of bronchospasm, which is typically associated with anaphylaxis.
Fortunately, both conditions can be treated similarly, and the strategic choice of epinephrine as the vasopressor, in this case, allowed for supportive treatment of suspected anaphylaxis while also covering the possibility of acute pulmonary embolus. Epinephrine is the first-line treatment for severe anaphylaxis because it decreases mediator release from mast cells, reverses the associated cardiovascular collapse that occurs secondary to increased vascular permeability, and reverses airflow obstruction and bronchospasm [5,9-10]. Early administration is key, as delays result in increased mortality [5-6]. In this case, boluses of epinephrine were given shortly after the initial event. For severe pulmonary embolism with hemodynamic instability, epinephrine is also considered a first-line agent (in addition to norepinephrine and isoproterenol). These medications, which increase contractility and are positive dromotropes, help mitigate the right ventricular overload and hemodynamic compromise, which can occur with a significant PE [8]. Interestingly, in this case, the patient’s CTA noted enlargement of the pulmonary artery and evidence of pulmonary hypertension. This indicates that the significant burden of her multiple pulmonary emboli may have contributed to the event.
This case was unique in that even after the workup that followed the critical event, it remains unclear whether the patient’s near-arrest occurred secondary to anaphylaxis or pulmonary emboli. The patient’s elevated tryptase of 14.4 ug/L was evidence of anaphylaxis. Tryptase, a serine protease released by mast cells, becomes elevated during acute anaphylaxis. While many centers consider the normal range for tryptase to be less than 11.4 ug/L, based on the manufacturer ThermoFisher (Waltham, Massachusetts), there is variability in this reference range, with some thresholds as low as 8.23 ug/L and others as high as 14 ug/L [11]. A recent study on intraoperative anaphylaxis found a threshold of 15.7 ug/L to be highly predictive of intraoperative anaphylaxis [12]. A 2010 consensus equation was developed by an international working group relating tryptase levels to baseline, where the upper limit for anaphylaxis would be considered > 1.2x baseline tryptase + 2 ug/L [11]. Unfortunately, in this case, we did not have a baseline for comparison. The value of 14.4 ug/L may or may not indicate significant elevation depending on the patient’s baseline, and the basal serum tryptase level is < 15 ug/L in 95% of the population [13]. The patient did have allergy testing, which confirmed a high degree of reactivity to cefazolin and she has since tolerated all other potential triggering medications without incident. The timing of cefazolin administration was consistent with the diagnose of anaphylaxis. Our search of the literature did not reveal a case report depicting both anaphylaxis and pulmonary embolus at the same time.
The patient was also diagnosed with multiple pulmonary emboli, a right lower extremity DVT, and a right upper extremity superficial venous thrombosis in the immediate workup that followed her near-arrest. She also had decreased AT activity and AT antigen levels indicative of type I AT deficiency. Given this newly diagnosed coagulopathy and evidence of pulmonary artery enlargement and pulmonary hypertension on CTA, it is certainly possible that acute pulmonary emboli could have caused the hypotension and near-arrest. It is also possible that acute anaphylaxis in the setting of pre-existing pulmonary emboli may be the true explanation of the patient’s near-arrest.
Conclusions
This complicated case of an intraoperative near-arrest in an otherwise healthy young woman during elective surgery underscores the importance of the differential diagnosis when critical events occur in the operating room. While we may never know the true cause of this untoward intraoperative event, suspected anaphylaxis versus acute pulmonary emboli, the astute anesthesiologist was able to rule out the least likely causes and provide treatment, with a clear benefit for both pathologic states. In medicine, the search for a clear diagnosis and answer can, at times, be convoluted or even impossible. This is the space in which experience, quick thinking, and a basic understanding of all potential possibilities can be life-saving, as was the case with this patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
We thank Mr. Thomas R. Finney, Executive Assistant, for technical assistance with the rendering of figures. | Recovered | ReactionOutcome | CC BY | 33665061 | 19,002,130 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | First case of Kluyveromyces marxianus (Candida kefyr) late onset keratitis after lamellar endothelial corneal graft.
We present a case of Kluyveromyces marxianus keratitis nine months after Descement's membrane endothelial keratoplasty (DMEK) in a patient with Fuchs endothelial disease. Endothelial scraping revealed this rare yeast infection at the interface between graft and host cornea. Immediate antifungal treatment with intracameral and corneal intrastromal injections of voriconazole and amphotericin B remained unsuccessful, requiring penetrating keratoplasty. This case highlights the challenging management of keratomycosis in patients with endothelial grafts.
1 Introduction
Keratomycosis is a severe sight-threatening eye infection, conferred by both Candida
species and filamentous fungi, which imposes a significant health issue of growing global concern [[1], [2], [3], [4], [5], [6]]. While keratomycosis is a relatively common event in tropical and subtropical regions, the incidence of fungal keratitis remains rare in moderate climate countries within Europe [2,5,6]. However, between 2003 and 2017 a 5-fold increase has been observed in different European countries, from 0.32 to 1.53 cases per million inhabitants per year [3,4].
Etiologically, “independent” (i.e. social, economic, regional) and personal risk factors including corneal trauma, usage of contact lenses, prolonged usage of steroid eyedrops, ocular surface diseases and previous corneal transplants can be differentiated [[1], [2], [3]]. Though contaminations of transplants with Candida
species leading to keratitis or endophthalmitis after partial or full keratoplasty are rare events, differences in tissue preparation and storage standards of corneal transplants might serve as a possible explanation. Furthermore, the fortification of storage media with antifungal substances is handled divergently in eye banks across Europe and the US [7].
The transplantation of a lamellar endothelial corneal graft (DMEK, descemet membrane endothelial keratoplasty) is a less invasive and less immunogenic standard technique in comparison to full thickness keratoplasty [8]. The diseased corneal host tissue is exchanged by a donor lamellar graft comprising the basal lamina with the endothelial cell monolayer. Yeast infections after graft insertion have been reported [7,9]. Especially in treatment of Fuchs endothelial dystrophy DMEK has increasingly evolved to a standard procedure due to good long-term efficacy and fast increase of visual acuity [10,11]. Fuchs dystrophy is characterized by bilateral loss of corneal endothelial cells causing vision loss due to corneal edema. If medical treatment is unsuccessful, corneal transplantation is required.
The dairy yeast and facultative opportunistic fungal pathogen Kluyveromyces marxianus (syn.: Candida kefyr) -formerly Candida pseudotropicalis- is rarely associated with human infection and scarcely described as transient eye flora [12,13]. Here we present a case of keratomycosis caused by Kluyveromyces marxianus after DMEK.
2 Case presentation
A 69-year-old male patient suffering from Fuchs endothelial dystrophy predominantly affecting the right eye was admitted to the ophthalmology department for elective DMEK, which was performed without any complications (day 0). Notably, 13 years earlier, the patient had undergone cataract surgery with insertion of an artificial lens as well as a trabeculectomy for pseudoexfoliation (PEX) glaucoma. In PEX glaucoma, metabolism of the extracellular matrix is disturbed. The deposition of fibrillary material causes instability of the lens zonula and an increase in intraocular pressure.
After DMEK surgery, dexamethasone eye drops (1mg/ml) were applied six times a day, tapered weekly till day 42, to prevent rejection and to prolong graft survival. The cornea cleared and visual acuity increased from 0.15 (20/125) to 0.5 (20/25) within the following three weeks.
After a symptom-free period of three months, a PEX-related luxation of the artificial lens occurred requiring lens exchange with implantation of an iris-fixated, retropupillar intraocular lens (day 104). The cornea remained clear postoperatively, visual acuity was 0.5 (20/25).
Almost nine months after DMEK (day 264), sudden pain of the right eye set in. Redness and corneal edema were initially interpreted as graft rejection and steroid eye drops were administered (day 279–285: prednisolone acetate 10 mg/ml four times daily; later changed to preservative-free dexamethasone eye drops 1 mg/ml three times daily, day 286–288).
As vision deteriorated further the patient was referred to our ophthalmology department on day 288. A dense whitish paracentral corneal infiltrate became evident, accompanied by an entirely opaque cornea due to stromal edema (Fig. 1A). Optical coherence tomography revealed a hyperdensity of 1.3 mm in diameter localized between graft and host cornea (Fig. 1B).Fig. 1 Late onset Kluyveromyces marxianus keratitis after lamellar corneal transplantation (DMEK, descemet membrane endothelial keratoplasty).
A. Clinical findings nearly 9 months (288 days) after DMEK surgery: Paracentral corneal infiltrate with surrounding corneal opacity due to epithelial and stromal edema.
B. Cross-section of the cornea by in vivo optical coherence tomography reveals localization of the infiltrate (1291 μm in diameter) between graft lamella and host cornea (Ep: epithelium, S: stroma, En: endothelial transplant lamella).
C. Fungal structures (red arrows) in Grocott stain with surrounding mild inflammation. (Ep: epithelium, S: stroma, En: endothelial transplant lamella). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
Based on these findings we decided to broaden the diagnostic approach by tapping the anterior chamber and acquire an endothelial scraping in the area of the DMEK lamella harbouring the suspicious infiltrate. Local therapy consisted of an hourly alternating antibiotic regimen (day 288–291: ofloxacin 3 mg/ml and gentamicin sulphate 5 mg/ml).
While initial Gram staining of the scraping material showed no evidence of microbial pathogens, typical small yeast-like white colonies were observed both on chromogenic media (CHROMagar, Becton Dickinson, USA), blood and chocolate agar after 24 hours of incubation at 36 °C. The species was then identified as Kluyveromyces marxianus by Matrix-Assisted Laser Desorption/Ionisation-Time of Flight (MALDI-TOF) mass spectrometry (MS) (Biomerieux Paris, France, VITEK MS database version 3.2) and finally confirmed via sequencing the internal transcribed spacer of the ribosomal DNA (ITS-rDNA). The ITS sequence of the isolate showed 100% identity with that of the ex-type strain of Kluyveromyces marxianus CBS 712 (GenBank accession number NR_111,251). The strain is deposited in the Jena Microbial Resource Collection (JMRC:NRZ:2921).
Immediate susceptibility testing was performed by VITEK 2 automated system (Biomerieux, Paris, France) using an AST-YS08 testing cartridge (acc. to CLSI). Additionally, Sensititre Yeast One YO10 microbroth dilution (acc. to CLSI) and a EUCAST broth microdilution were conducted (Table 1).Table 1 Kluyveromyces marxianus (syn.: Candida kefyr) susceptibility testing results after 24h. Antifungal agents: anidulafungin (AND), amphotericin B (AMB), micafungin (MIC), caspofungin (CAS), 5-flucytosine (5-FC), posaconazole (POS), voriconazole (VOR), itraconazole (IT), fluconazole (FLU).
Table 1Testing method Acc. to reference method Minimal inhibitory concentrations (MICs) of antifungal agent (μg/ml)
AND AMB MIC CAS 5-FC POS VOR IT FLU
VITEK 2 CLSI – 0.5 0.12 – – – ≤0.12 – 1
YO CLSI 0.12 1 0.12 0.12 ≤0.06 0.12 ≤0.06 0.12 0.5
Broth Microdilution EUCAST 0.03 0.125 – – – ≤0.016 ≤0.016 ≤0.016 0.5
A combination therapy of oral fluconazole (day 291 onwards: 400 mg daily loading dose; 200 mg daily maintenance dose) and hourly eye drops with voriconazole (1%) were begun followed by regular voriconazole (2%) injections. A total of four voriconazole injections were administered intracamerally, intrastromally and subconjunctivally (day 292, 294, 299, 301).
Unfortunately, the infiltrate remained refractory to this treatment, even after regimen was switched to amphotericin B (50 μg/ml in 0.1ml) injections (day 305). On day 306, emergency full thickness keratoplasty had to be performed, again followed by intracameral application of amphotericin B.
The explanted graft revealed a slightly discontinuous Descemet membrane, whereas the multilayered corneal epithelium showed no significant abnormalities. Histopathology confirmed Candida infection. Fungal structures (red arrows) were identified in both PAS and Grocott stain with surrounding mild inflammation (Fig. 1C).
After keratoplasty, the new graft showed no evidence of recurrence. As prophylaxis, antifungal therapy was continued with hourly application of topical voriconazole (1%) and two intracameral injections of amphotericin B (50 μg/ml in 0.1ml, day 319 and 322). For the remaining follow-up period up to day 354, findings were stable without signs of fungal activity, so that antimycotic topical and systemic therapy was discontinued.
3 Discussion
Yeast infection is a rare complication of DMEK, occurring in 0.15% of the cases [14]. In the majority, causative pathogens can be obtained from direct biopsy. However, recent studies indicate that Candida-positive cultures of the corneal donor rim (tissue left over from transplantation) may be a valuable parameter in predicting fungal keratitis prior to the onset of clinical symptoms [7]. However, our patient developed no evidence of infection even four weeks after surgery, and neither did the donor rim show any signs of infection and was therefore discarded. This procedure is supported by the fact that longer preservation time is not necessarily correlated with higher incidences of donor rim contamination. In fact, only a small fraction of cases with positive donor rim cultures develop post-keratoplasty infection [15]. Therefore, it remains debatable whether the patient would have benefited from a prolonged donor cornea conservation.
Kluyveromyces marxianus is a rare but severe and life-threatening cause of bloodstream infection, which is underlined by the fact that Kluyveromyces marxianus candidiasis is associated with a higher mortality in ICU patients compared to C. albicans [16]. Hematologic malignancies are considered as a risk factor. Interestingly, a seasonal peak of colonisation and infection is observed during summertime, which might be related to a lack of refrigeration in dairy products [13].
In our case the patient developed first symptoms of keratitis nine months after DMEK. Fontana et al. described onset of bacterial or fungal keratitis as late as four months after surgery [17]. The special localization of the yeast sequestered between graft and host cornea could influence the late onset of infection and makes it less accessible by topical or systemic therapy [7,9]. However, therapeutic approaches do exist combining systemic therapy with multiple intrastromal and intracameral antimycotic injections, avoiding full thickness keratoplasty in Candida lamellar infection [9].
Despite some Kluyveromyces marxianus in vitro data, no official breakpoints are established due to the paucity of clinical, pharmaceutical and epidemiological information [18]. Only EUCAST provides one fluconazole non-species related breakpoint for Candida based upon PK/PD data, which is defined as susceptible ≤2 μg/ml.
Our antifungal regimen included oral administration of fluconazole accompanied by intracameral and intrastromal injections of voriconazole, which was considered effective -at least in vitro- according to the susceptibility data (Table 1).
Previous case reports clearly indicate that intracorneal injections of voriconazole are useful alternatives challenging deep stromal Candida infections, especially when full thickness keratoplasty is clinically thought to be too invasive at that particular timepoint [19]. Voriconazole is reported effective against different Candida species in-vitro, but overall pharmacokinetic and pharmacodynamic data is limited. Even so, experimental studies suggest a demand of repeated drug administration at the site of infection, due the risk of accelerated loss of concentration below MIC of common fungi, which we met with multiple intracarmal and intrastromal injections [20]. Fluconazole was given as an attempt to further strengthen local azole concentrations, being aware that corneal drug penetrations of systemically added antifungals are usually poor.
Notably, comparing both EUCAST and CLSI methodologies performed on different testing devices (in-house broth microdilution versus semiautomatic- and automatic commercial broth microdilution), obtained minimum inhibitory concentrations (MICs) are in a similar range.
A change to amphotericin B was considered as a last attempt for medical treatment. It is debatable whether this change should have been considered earlier or even in first place, but it illustrates the dilemma of susceptibility testing in vitro and the concordant effect in vivo at the site of infection.
Nonetheless, graft removal was inevitable, underlining the complexity of treating this rare infection by constantly re-balancing the value of antifungal therapy with the lack of in vivo breakpoints against surgical measures, which will ultimately remove the infected focus but result in a new full thickness graft with a risk of reinfection and other complications.
Further interdisciplinary clinical studies and case reports are warranted not only to elucidate the role of Kluyveromyces marxianus as a rare pathogen but also to develop new treatment strategies for this challenging infection.
Funding source
The German National Reference Center NRZMyk is funded by the Robert Koch Institute from funds provided by the 10.13039/501100003107German Ministry of Health (grant no. 1369-240).
Consent
Written informed consent was obtained from the patient or legal guardian(s) for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Declaration of competing interest
There are none.
Acknowledgements
We thank Anastasia Besenfelder, Sabrina Mündlein for generating the susceptibility data and Ronny Martin, Yano Axel Pöhlmann for critically reviewing the manuscript. | FLUCONAZOLE, VORICONAZOLE | DrugsGivenReaction | CC BY | 33665066 | 19,052,023 | 2021-06 |
What was the administration route of drug 'FLUCONAZOLE'? | First case of Kluyveromyces marxianus (Candida kefyr) late onset keratitis after lamellar endothelial corneal graft.
We present a case of Kluyveromyces marxianus keratitis nine months after Descement's membrane endothelial keratoplasty (DMEK) in a patient with Fuchs endothelial disease. Endothelial scraping revealed this rare yeast infection at the interface between graft and host cornea. Immediate antifungal treatment with intracameral and corneal intrastromal injections of voriconazole and amphotericin B remained unsuccessful, requiring penetrating keratoplasty. This case highlights the challenging management of keratomycosis in patients with endothelial grafts.
1 Introduction
Keratomycosis is a severe sight-threatening eye infection, conferred by both Candida
species and filamentous fungi, which imposes a significant health issue of growing global concern [[1], [2], [3], [4], [5], [6]]. While keratomycosis is a relatively common event in tropical and subtropical regions, the incidence of fungal keratitis remains rare in moderate climate countries within Europe [2,5,6]. However, between 2003 and 2017 a 5-fold increase has been observed in different European countries, from 0.32 to 1.53 cases per million inhabitants per year [3,4].
Etiologically, “independent” (i.e. social, economic, regional) and personal risk factors including corneal trauma, usage of contact lenses, prolonged usage of steroid eyedrops, ocular surface diseases and previous corneal transplants can be differentiated [[1], [2], [3]]. Though contaminations of transplants with Candida
species leading to keratitis or endophthalmitis after partial or full keratoplasty are rare events, differences in tissue preparation and storage standards of corneal transplants might serve as a possible explanation. Furthermore, the fortification of storage media with antifungal substances is handled divergently in eye banks across Europe and the US [7].
The transplantation of a lamellar endothelial corneal graft (DMEK, descemet membrane endothelial keratoplasty) is a less invasive and less immunogenic standard technique in comparison to full thickness keratoplasty [8]. The diseased corneal host tissue is exchanged by a donor lamellar graft comprising the basal lamina with the endothelial cell monolayer. Yeast infections after graft insertion have been reported [7,9]. Especially in treatment of Fuchs endothelial dystrophy DMEK has increasingly evolved to a standard procedure due to good long-term efficacy and fast increase of visual acuity [10,11]. Fuchs dystrophy is characterized by bilateral loss of corneal endothelial cells causing vision loss due to corneal edema. If medical treatment is unsuccessful, corneal transplantation is required.
The dairy yeast and facultative opportunistic fungal pathogen Kluyveromyces marxianus (syn.: Candida kefyr) -formerly Candida pseudotropicalis- is rarely associated with human infection and scarcely described as transient eye flora [12,13]. Here we present a case of keratomycosis caused by Kluyveromyces marxianus after DMEK.
2 Case presentation
A 69-year-old male patient suffering from Fuchs endothelial dystrophy predominantly affecting the right eye was admitted to the ophthalmology department for elective DMEK, which was performed without any complications (day 0). Notably, 13 years earlier, the patient had undergone cataract surgery with insertion of an artificial lens as well as a trabeculectomy for pseudoexfoliation (PEX) glaucoma. In PEX glaucoma, metabolism of the extracellular matrix is disturbed. The deposition of fibrillary material causes instability of the lens zonula and an increase in intraocular pressure.
After DMEK surgery, dexamethasone eye drops (1mg/ml) were applied six times a day, tapered weekly till day 42, to prevent rejection and to prolong graft survival. The cornea cleared and visual acuity increased from 0.15 (20/125) to 0.5 (20/25) within the following three weeks.
After a symptom-free period of three months, a PEX-related luxation of the artificial lens occurred requiring lens exchange with implantation of an iris-fixated, retropupillar intraocular lens (day 104). The cornea remained clear postoperatively, visual acuity was 0.5 (20/25).
Almost nine months after DMEK (day 264), sudden pain of the right eye set in. Redness and corneal edema were initially interpreted as graft rejection and steroid eye drops were administered (day 279–285: prednisolone acetate 10 mg/ml four times daily; later changed to preservative-free dexamethasone eye drops 1 mg/ml three times daily, day 286–288).
As vision deteriorated further the patient was referred to our ophthalmology department on day 288. A dense whitish paracentral corneal infiltrate became evident, accompanied by an entirely opaque cornea due to stromal edema (Fig. 1A). Optical coherence tomography revealed a hyperdensity of 1.3 mm in diameter localized between graft and host cornea (Fig. 1B).Fig. 1 Late onset Kluyveromyces marxianus keratitis after lamellar corneal transplantation (DMEK, descemet membrane endothelial keratoplasty).
A. Clinical findings nearly 9 months (288 days) after DMEK surgery: Paracentral corneal infiltrate with surrounding corneal opacity due to epithelial and stromal edema.
B. Cross-section of the cornea by in vivo optical coherence tomography reveals localization of the infiltrate (1291 μm in diameter) between graft lamella and host cornea (Ep: epithelium, S: stroma, En: endothelial transplant lamella).
C. Fungal structures (red arrows) in Grocott stain with surrounding mild inflammation. (Ep: epithelium, S: stroma, En: endothelial transplant lamella). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
Based on these findings we decided to broaden the diagnostic approach by tapping the anterior chamber and acquire an endothelial scraping in the area of the DMEK lamella harbouring the suspicious infiltrate. Local therapy consisted of an hourly alternating antibiotic regimen (day 288–291: ofloxacin 3 mg/ml and gentamicin sulphate 5 mg/ml).
While initial Gram staining of the scraping material showed no evidence of microbial pathogens, typical small yeast-like white colonies were observed both on chromogenic media (CHROMagar, Becton Dickinson, USA), blood and chocolate agar after 24 hours of incubation at 36 °C. The species was then identified as Kluyveromyces marxianus by Matrix-Assisted Laser Desorption/Ionisation-Time of Flight (MALDI-TOF) mass spectrometry (MS) (Biomerieux Paris, France, VITEK MS database version 3.2) and finally confirmed via sequencing the internal transcribed spacer of the ribosomal DNA (ITS-rDNA). The ITS sequence of the isolate showed 100% identity with that of the ex-type strain of Kluyveromyces marxianus CBS 712 (GenBank accession number NR_111,251). The strain is deposited in the Jena Microbial Resource Collection (JMRC:NRZ:2921).
Immediate susceptibility testing was performed by VITEK 2 automated system (Biomerieux, Paris, France) using an AST-YS08 testing cartridge (acc. to CLSI). Additionally, Sensititre Yeast One YO10 microbroth dilution (acc. to CLSI) and a EUCAST broth microdilution were conducted (Table 1).Table 1 Kluyveromyces marxianus (syn.: Candida kefyr) susceptibility testing results after 24h. Antifungal agents: anidulafungin (AND), amphotericin B (AMB), micafungin (MIC), caspofungin (CAS), 5-flucytosine (5-FC), posaconazole (POS), voriconazole (VOR), itraconazole (IT), fluconazole (FLU).
Table 1Testing method Acc. to reference method Minimal inhibitory concentrations (MICs) of antifungal agent (μg/ml)
AND AMB MIC CAS 5-FC POS VOR IT FLU
VITEK 2 CLSI – 0.5 0.12 – – – ≤0.12 – 1
YO CLSI 0.12 1 0.12 0.12 ≤0.06 0.12 ≤0.06 0.12 0.5
Broth Microdilution EUCAST 0.03 0.125 – – – ≤0.016 ≤0.016 ≤0.016 0.5
A combination therapy of oral fluconazole (day 291 onwards: 400 mg daily loading dose; 200 mg daily maintenance dose) and hourly eye drops with voriconazole (1%) were begun followed by regular voriconazole (2%) injections. A total of four voriconazole injections were administered intracamerally, intrastromally and subconjunctivally (day 292, 294, 299, 301).
Unfortunately, the infiltrate remained refractory to this treatment, even after regimen was switched to amphotericin B (50 μg/ml in 0.1ml) injections (day 305). On day 306, emergency full thickness keratoplasty had to be performed, again followed by intracameral application of amphotericin B.
The explanted graft revealed a slightly discontinuous Descemet membrane, whereas the multilayered corneal epithelium showed no significant abnormalities. Histopathology confirmed Candida infection. Fungal structures (red arrows) were identified in both PAS and Grocott stain with surrounding mild inflammation (Fig. 1C).
After keratoplasty, the new graft showed no evidence of recurrence. As prophylaxis, antifungal therapy was continued with hourly application of topical voriconazole (1%) and two intracameral injections of amphotericin B (50 μg/ml in 0.1ml, day 319 and 322). For the remaining follow-up period up to day 354, findings were stable without signs of fungal activity, so that antimycotic topical and systemic therapy was discontinued.
3 Discussion
Yeast infection is a rare complication of DMEK, occurring in 0.15% of the cases [14]. In the majority, causative pathogens can be obtained from direct biopsy. However, recent studies indicate that Candida-positive cultures of the corneal donor rim (tissue left over from transplantation) may be a valuable parameter in predicting fungal keratitis prior to the onset of clinical symptoms [7]. However, our patient developed no evidence of infection even four weeks after surgery, and neither did the donor rim show any signs of infection and was therefore discarded. This procedure is supported by the fact that longer preservation time is not necessarily correlated with higher incidences of donor rim contamination. In fact, only a small fraction of cases with positive donor rim cultures develop post-keratoplasty infection [15]. Therefore, it remains debatable whether the patient would have benefited from a prolonged donor cornea conservation.
Kluyveromyces marxianus is a rare but severe and life-threatening cause of bloodstream infection, which is underlined by the fact that Kluyveromyces marxianus candidiasis is associated with a higher mortality in ICU patients compared to C. albicans [16]. Hematologic malignancies are considered as a risk factor. Interestingly, a seasonal peak of colonisation and infection is observed during summertime, which might be related to a lack of refrigeration in dairy products [13].
In our case the patient developed first symptoms of keratitis nine months after DMEK. Fontana et al. described onset of bacterial or fungal keratitis as late as four months after surgery [17]. The special localization of the yeast sequestered between graft and host cornea could influence the late onset of infection and makes it less accessible by topical or systemic therapy [7,9]. However, therapeutic approaches do exist combining systemic therapy with multiple intrastromal and intracameral antimycotic injections, avoiding full thickness keratoplasty in Candida lamellar infection [9].
Despite some Kluyveromyces marxianus in vitro data, no official breakpoints are established due to the paucity of clinical, pharmaceutical and epidemiological information [18]. Only EUCAST provides one fluconazole non-species related breakpoint for Candida based upon PK/PD data, which is defined as susceptible ≤2 μg/ml.
Our antifungal regimen included oral administration of fluconazole accompanied by intracameral and intrastromal injections of voriconazole, which was considered effective -at least in vitro- according to the susceptibility data (Table 1).
Previous case reports clearly indicate that intracorneal injections of voriconazole are useful alternatives challenging deep stromal Candida infections, especially when full thickness keratoplasty is clinically thought to be too invasive at that particular timepoint [19]. Voriconazole is reported effective against different Candida species in-vitro, but overall pharmacokinetic and pharmacodynamic data is limited. Even so, experimental studies suggest a demand of repeated drug administration at the site of infection, due the risk of accelerated loss of concentration below MIC of common fungi, which we met with multiple intracarmal and intrastromal injections [20]. Fluconazole was given as an attempt to further strengthen local azole concentrations, being aware that corneal drug penetrations of systemically added antifungals are usually poor.
Notably, comparing both EUCAST and CLSI methodologies performed on different testing devices (in-house broth microdilution versus semiautomatic- and automatic commercial broth microdilution), obtained minimum inhibitory concentrations (MICs) are in a similar range.
A change to amphotericin B was considered as a last attempt for medical treatment. It is debatable whether this change should have been considered earlier or even in first place, but it illustrates the dilemma of susceptibility testing in vitro and the concordant effect in vivo at the site of infection.
Nonetheless, graft removal was inevitable, underlining the complexity of treating this rare infection by constantly re-balancing the value of antifungal therapy with the lack of in vivo breakpoints against surgical measures, which will ultimately remove the infected focus but result in a new full thickness graft with a risk of reinfection and other complications.
Further interdisciplinary clinical studies and case reports are warranted not only to elucidate the role of Kluyveromyces marxianus as a rare pathogen but also to develop new treatment strategies for this challenging infection.
Funding source
The German National Reference Center NRZMyk is funded by the Robert Koch Institute from funds provided by the 10.13039/501100003107German Ministry of Health (grant no. 1369-240).
Consent
Written informed consent was obtained from the patient or legal guardian(s) for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Declaration of competing interest
There are none.
Acknowledgements
We thank Anastasia Besenfelder, Sabrina Mündlein for generating the susceptibility data and Ronny Martin, Yano Axel Pöhlmann for critically reviewing the manuscript. | Oral | DrugAdministrationRoute | CC BY | 33665066 | 19,052,023 | 2021-06 |
What was the dosage of drug 'FLUCONAZOLE'? | First case of Kluyveromyces marxianus (Candida kefyr) late onset keratitis after lamellar endothelial corneal graft.
We present a case of Kluyveromyces marxianus keratitis nine months after Descement's membrane endothelial keratoplasty (DMEK) in a patient with Fuchs endothelial disease. Endothelial scraping revealed this rare yeast infection at the interface between graft and host cornea. Immediate antifungal treatment with intracameral and corneal intrastromal injections of voriconazole and amphotericin B remained unsuccessful, requiring penetrating keratoplasty. This case highlights the challenging management of keratomycosis in patients with endothelial grafts.
1 Introduction
Keratomycosis is a severe sight-threatening eye infection, conferred by both Candida
species and filamentous fungi, which imposes a significant health issue of growing global concern [[1], [2], [3], [4], [5], [6]]. While keratomycosis is a relatively common event in tropical and subtropical regions, the incidence of fungal keratitis remains rare in moderate climate countries within Europe [2,5,6]. However, between 2003 and 2017 a 5-fold increase has been observed in different European countries, from 0.32 to 1.53 cases per million inhabitants per year [3,4].
Etiologically, “independent” (i.e. social, economic, regional) and personal risk factors including corneal trauma, usage of contact lenses, prolonged usage of steroid eyedrops, ocular surface diseases and previous corneal transplants can be differentiated [[1], [2], [3]]. Though contaminations of transplants with Candida
species leading to keratitis or endophthalmitis after partial or full keratoplasty are rare events, differences in tissue preparation and storage standards of corneal transplants might serve as a possible explanation. Furthermore, the fortification of storage media with antifungal substances is handled divergently in eye banks across Europe and the US [7].
The transplantation of a lamellar endothelial corneal graft (DMEK, descemet membrane endothelial keratoplasty) is a less invasive and less immunogenic standard technique in comparison to full thickness keratoplasty [8]. The diseased corneal host tissue is exchanged by a donor lamellar graft comprising the basal lamina with the endothelial cell monolayer. Yeast infections after graft insertion have been reported [7,9]. Especially in treatment of Fuchs endothelial dystrophy DMEK has increasingly evolved to a standard procedure due to good long-term efficacy and fast increase of visual acuity [10,11]. Fuchs dystrophy is characterized by bilateral loss of corneal endothelial cells causing vision loss due to corneal edema. If medical treatment is unsuccessful, corneal transplantation is required.
The dairy yeast and facultative opportunistic fungal pathogen Kluyveromyces marxianus (syn.: Candida kefyr) -formerly Candida pseudotropicalis- is rarely associated with human infection and scarcely described as transient eye flora [12,13]. Here we present a case of keratomycosis caused by Kluyveromyces marxianus after DMEK.
2 Case presentation
A 69-year-old male patient suffering from Fuchs endothelial dystrophy predominantly affecting the right eye was admitted to the ophthalmology department for elective DMEK, which was performed without any complications (day 0). Notably, 13 years earlier, the patient had undergone cataract surgery with insertion of an artificial lens as well as a trabeculectomy for pseudoexfoliation (PEX) glaucoma. In PEX glaucoma, metabolism of the extracellular matrix is disturbed. The deposition of fibrillary material causes instability of the lens zonula and an increase in intraocular pressure.
After DMEK surgery, dexamethasone eye drops (1mg/ml) were applied six times a day, tapered weekly till day 42, to prevent rejection and to prolong graft survival. The cornea cleared and visual acuity increased from 0.15 (20/125) to 0.5 (20/25) within the following three weeks.
After a symptom-free period of three months, a PEX-related luxation of the artificial lens occurred requiring lens exchange with implantation of an iris-fixated, retropupillar intraocular lens (day 104). The cornea remained clear postoperatively, visual acuity was 0.5 (20/25).
Almost nine months after DMEK (day 264), sudden pain of the right eye set in. Redness and corneal edema were initially interpreted as graft rejection and steroid eye drops were administered (day 279–285: prednisolone acetate 10 mg/ml four times daily; later changed to preservative-free dexamethasone eye drops 1 mg/ml three times daily, day 286–288).
As vision deteriorated further the patient was referred to our ophthalmology department on day 288. A dense whitish paracentral corneal infiltrate became evident, accompanied by an entirely opaque cornea due to stromal edema (Fig. 1A). Optical coherence tomography revealed a hyperdensity of 1.3 mm in diameter localized between graft and host cornea (Fig. 1B).Fig. 1 Late onset Kluyveromyces marxianus keratitis after lamellar corneal transplantation (DMEK, descemet membrane endothelial keratoplasty).
A. Clinical findings nearly 9 months (288 days) after DMEK surgery: Paracentral corneal infiltrate with surrounding corneal opacity due to epithelial and stromal edema.
B. Cross-section of the cornea by in vivo optical coherence tomography reveals localization of the infiltrate (1291 μm in diameter) between graft lamella and host cornea (Ep: epithelium, S: stroma, En: endothelial transplant lamella).
C. Fungal structures (red arrows) in Grocott stain with surrounding mild inflammation. (Ep: epithelium, S: stroma, En: endothelial transplant lamella). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
Based on these findings we decided to broaden the diagnostic approach by tapping the anterior chamber and acquire an endothelial scraping in the area of the DMEK lamella harbouring the suspicious infiltrate. Local therapy consisted of an hourly alternating antibiotic regimen (day 288–291: ofloxacin 3 mg/ml and gentamicin sulphate 5 mg/ml).
While initial Gram staining of the scraping material showed no evidence of microbial pathogens, typical small yeast-like white colonies were observed both on chromogenic media (CHROMagar, Becton Dickinson, USA), blood and chocolate agar after 24 hours of incubation at 36 °C. The species was then identified as Kluyveromyces marxianus by Matrix-Assisted Laser Desorption/Ionisation-Time of Flight (MALDI-TOF) mass spectrometry (MS) (Biomerieux Paris, France, VITEK MS database version 3.2) and finally confirmed via sequencing the internal transcribed spacer of the ribosomal DNA (ITS-rDNA). The ITS sequence of the isolate showed 100% identity with that of the ex-type strain of Kluyveromyces marxianus CBS 712 (GenBank accession number NR_111,251). The strain is deposited in the Jena Microbial Resource Collection (JMRC:NRZ:2921).
Immediate susceptibility testing was performed by VITEK 2 automated system (Biomerieux, Paris, France) using an AST-YS08 testing cartridge (acc. to CLSI). Additionally, Sensititre Yeast One YO10 microbroth dilution (acc. to CLSI) and a EUCAST broth microdilution were conducted (Table 1).Table 1 Kluyveromyces marxianus (syn.: Candida kefyr) susceptibility testing results after 24h. Antifungal agents: anidulafungin (AND), amphotericin B (AMB), micafungin (MIC), caspofungin (CAS), 5-flucytosine (5-FC), posaconazole (POS), voriconazole (VOR), itraconazole (IT), fluconazole (FLU).
Table 1Testing method Acc. to reference method Minimal inhibitory concentrations (MICs) of antifungal agent (μg/ml)
AND AMB MIC CAS 5-FC POS VOR IT FLU
VITEK 2 CLSI – 0.5 0.12 – – – ≤0.12 – 1
YO CLSI 0.12 1 0.12 0.12 ≤0.06 0.12 ≤0.06 0.12 0.5
Broth Microdilution EUCAST 0.03 0.125 – – – ≤0.016 ≤0.016 ≤0.016 0.5
A combination therapy of oral fluconazole (day 291 onwards: 400 mg daily loading dose; 200 mg daily maintenance dose) and hourly eye drops with voriconazole (1%) were begun followed by regular voriconazole (2%) injections. A total of four voriconazole injections were administered intracamerally, intrastromally and subconjunctivally (day 292, 294, 299, 301).
Unfortunately, the infiltrate remained refractory to this treatment, even after regimen was switched to amphotericin B (50 μg/ml in 0.1ml) injections (day 305). On day 306, emergency full thickness keratoplasty had to be performed, again followed by intracameral application of amphotericin B.
The explanted graft revealed a slightly discontinuous Descemet membrane, whereas the multilayered corneal epithelium showed no significant abnormalities. Histopathology confirmed Candida infection. Fungal structures (red arrows) were identified in both PAS and Grocott stain with surrounding mild inflammation (Fig. 1C).
After keratoplasty, the new graft showed no evidence of recurrence. As prophylaxis, antifungal therapy was continued with hourly application of topical voriconazole (1%) and two intracameral injections of amphotericin B (50 μg/ml in 0.1ml, day 319 and 322). For the remaining follow-up period up to day 354, findings were stable without signs of fungal activity, so that antimycotic topical and systemic therapy was discontinued.
3 Discussion
Yeast infection is a rare complication of DMEK, occurring in 0.15% of the cases [14]. In the majority, causative pathogens can be obtained from direct biopsy. However, recent studies indicate that Candida-positive cultures of the corneal donor rim (tissue left over from transplantation) may be a valuable parameter in predicting fungal keratitis prior to the onset of clinical symptoms [7]. However, our patient developed no evidence of infection even four weeks after surgery, and neither did the donor rim show any signs of infection and was therefore discarded. This procedure is supported by the fact that longer preservation time is not necessarily correlated with higher incidences of donor rim contamination. In fact, only a small fraction of cases with positive donor rim cultures develop post-keratoplasty infection [15]. Therefore, it remains debatable whether the patient would have benefited from a prolonged donor cornea conservation.
Kluyveromyces marxianus is a rare but severe and life-threatening cause of bloodstream infection, which is underlined by the fact that Kluyveromyces marxianus candidiasis is associated with a higher mortality in ICU patients compared to C. albicans [16]. Hematologic malignancies are considered as a risk factor. Interestingly, a seasonal peak of colonisation and infection is observed during summertime, which might be related to a lack of refrigeration in dairy products [13].
In our case the patient developed first symptoms of keratitis nine months after DMEK. Fontana et al. described onset of bacterial or fungal keratitis as late as four months after surgery [17]. The special localization of the yeast sequestered between graft and host cornea could influence the late onset of infection and makes it less accessible by topical or systemic therapy [7,9]. However, therapeutic approaches do exist combining systemic therapy with multiple intrastromal and intracameral antimycotic injections, avoiding full thickness keratoplasty in Candida lamellar infection [9].
Despite some Kluyveromyces marxianus in vitro data, no official breakpoints are established due to the paucity of clinical, pharmaceutical and epidemiological information [18]. Only EUCAST provides one fluconazole non-species related breakpoint for Candida based upon PK/PD data, which is defined as susceptible ≤2 μg/ml.
Our antifungal regimen included oral administration of fluconazole accompanied by intracameral and intrastromal injections of voriconazole, which was considered effective -at least in vitro- according to the susceptibility data (Table 1).
Previous case reports clearly indicate that intracorneal injections of voriconazole are useful alternatives challenging deep stromal Candida infections, especially when full thickness keratoplasty is clinically thought to be too invasive at that particular timepoint [19]. Voriconazole is reported effective against different Candida species in-vitro, but overall pharmacokinetic and pharmacodynamic data is limited. Even so, experimental studies suggest a demand of repeated drug administration at the site of infection, due the risk of accelerated loss of concentration below MIC of common fungi, which we met with multiple intracarmal and intrastromal injections [20]. Fluconazole was given as an attempt to further strengthen local azole concentrations, being aware that corneal drug penetrations of systemically added antifungals are usually poor.
Notably, comparing both EUCAST and CLSI methodologies performed on different testing devices (in-house broth microdilution versus semiautomatic- and automatic commercial broth microdilution), obtained minimum inhibitory concentrations (MICs) are in a similar range.
A change to amphotericin B was considered as a last attempt for medical treatment. It is debatable whether this change should have been considered earlier or even in first place, but it illustrates the dilemma of susceptibility testing in vitro and the concordant effect in vivo at the site of infection.
Nonetheless, graft removal was inevitable, underlining the complexity of treating this rare infection by constantly re-balancing the value of antifungal therapy with the lack of in vivo breakpoints against surgical measures, which will ultimately remove the infected focus but result in a new full thickness graft with a risk of reinfection and other complications.
Further interdisciplinary clinical studies and case reports are warranted not only to elucidate the role of Kluyveromyces marxianus as a rare pathogen but also to develop new treatment strategies for this challenging infection.
Funding source
The German National Reference Center NRZMyk is funded by the Robert Koch Institute from funds provided by the 10.13039/501100003107German Ministry of Health (grant no. 1369-240).
Consent
Written informed consent was obtained from the patient or legal guardian(s) for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Declaration of competing interest
There are none.
Acknowledgements
We thank Anastasia Besenfelder, Sabrina Mündlein for generating the susceptibility data and Ronny Martin, Yano Axel Pöhlmann for critically reviewing the manuscript. | 400 mg (milligrams). | DrugDosage | CC BY | 33665066 | 19,052,023 | 2021-06 |
What was the dosage of drug 'VORICONAZOLE'? | First case of Kluyveromyces marxianus (Candida kefyr) late onset keratitis after lamellar endothelial corneal graft.
We present a case of Kluyveromyces marxianus keratitis nine months after Descement's membrane endothelial keratoplasty (DMEK) in a patient with Fuchs endothelial disease. Endothelial scraping revealed this rare yeast infection at the interface between graft and host cornea. Immediate antifungal treatment with intracameral and corneal intrastromal injections of voriconazole and amphotericin B remained unsuccessful, requiring penetrating keratoplasty. This case highlights the challenging management of keratomycosis in patients with endothelial grafts.
1 Introduction
Keratomycosis is a severe sight-threatening eye infection, conferred by both Candida
species and filamentous fungi, which imposes a significant health issue of growing global concern [[1], [2], [3], [4], [5], [6]]. While keratomycosis is a relatively common event in tropical and subtropical regions, the incidence of fungal keratitis remains rare in moderate climate countries within Europe [2,5,6]. However, between 2003 and 2017 a 5-fold increase has been observed in different European countries, from 0.32 to 1.53 cases per million inhabitants per year [3,4].
Etiologically, “independent” (i.e. social, economic, regional) and personal risk factors including corneal trauma, usage of contact lenses, prolonged usage of steroid eyedrops, ocular surface diseases and previous corneal transplants can be differentiated [[1], [2], [3]]. Though contaminations of transplants with Candida
species leading to keratitis or endophthalmitis after partial or full keratoplasty are rare events, differences in tissue preparation and storage standards of corneal transplants might serve as a possible explanation. Furthermore, the fortification of storage media with antifungal substances is handled divergently in eye banks across Europe and the US [7].
The transplantation of a lamellar endothelial corneal graft (DMEK, descemet membrane endothelial keratoplasty) is a less invasive and less immunogenic standard technique in comparison to full thickness keratoplasty [8]. The diseased corneal host tissue is exchanged by a donor lamellar graft comprising the basal lamina with the endothelial cell monolayer. Yeast infections after graft insertion have been reported [7,9]. Especially in treatment of Fuchs endothelial dystrophy DMEK has increasingly evolved to a standard procedure due to good long-term efficacy and fast increase of visual acuity [10,11]. Fuchs dystrophy is characterized by bilateral loss of corneal endothelial cells causing vision loss due to corneal edema. If medical treatment is unsuccessful, corneal transplantation is required.
The dairy yeast and facultative opportunistic fungal pathogen Kluyveromyces marxianus (syn.: Candida kefyr) -formerly Candida pseudotropicalis- is rarely associated with human infection and scarcely described as transient eye flora [12,13]. Here we present a case of keratomycosis caused by Kluyveromyces marxianus after DMEK.
2 Case presentation
A 69-year-old male patient suffering from Fuchs endothelial dystrophy predominantly affecting the right eye was admitted to the ophthalmology department for elective DMEK, which was performed without any complications (day 0). Notably, 13 years earlier, the patient had undergone cataract surgery with insertion of an artificial lens as well as a trabeculectomy for pseudoexfoliation (PEX) glaucoma. In PEX glaucoma, metabolism of the extracellular matrix is disturbed. The deposition of fibrillary material causes instability of the lens zonula and an increase in intraocular pressure.
After DMEK surgery, dexamethasone eye drops (1mg/ml) were applied six times a day, tapered weekly till day 42, to prevent rejection and to prolong graft survival. The cornea cleared and visual acuity increased from 0.15 (20/125) to 0.5 (20/25) within the following three weeks.
After a symptom-free period of three months, a PEX-related luxation of the artificial lens occurred requiring lens exchange with implantation of an iris-fixated, retropupillar intraocular lens (day 104). The cornea remained clear postoperatively, visual acuity was 0.5 (20/25).
Almost nine months after DMEK (day 264), sudden pain of the right eye set in. Redness and corneal edema were initially interpreted as graft rejection and steroid eye drops were administered (day 279–285: prednisolone acetate 10 mg/ml four times daily; later changed to preservative-free dexamethasone eye drops 1 mg/ml three times daily, day 286–288).
As vision deteriorated further the patient was referred to our ophthalmology department on day 288. A dense whitish paracentral corneal infiltrate became evident, accompanied by an entirely opaque cornea due to stromal edema (Fig. 1A). Optical coherence tomography revealed a hyperdensity of 1.3 mm in diameter localized between graft and host cornea (Fig. 1B).Fig. 1 Late onset Kluyveromyces marxianus keratitis after lamellar corneal transplantation (DMEK, descemet membrane endothelial keratoplasty).
A. Clinical findings nearly 9 months (288 days) after DMEK surgery: Paracentral corneal infiltrate with surrounding corneal opacity due to epithelial and stromal edema.
B. Cross-section of the cornea by in vivo optical coherence tomography reveals localization of the infiltrate (1291 μm in diameter) between graft lamella and host cornea (Ep: epithelium, S: stroma, En: endothelial transplant lamella).
C. Fungal structures (red arrows) in Grocott stain with surrounding mild inflammation. (Ep: epithelium, S: stroma, En: endothelial transplant lamella). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
Based on these findings we decided to broaden the diagnostic approach by tapping the anterior chamber and acquire an endothelial scraping in the area of the DMEK lamella harbouring the suspicious infiltrate. Local therapy consisted of an hourly alternating antibiotic regimen (day 288–291: ofloxacin 3 mg/ml and gentamicin sulphate 5 mg/ml).
While initial Gram staining of the scraping material showed no evidence of microbial pathogens, typical small yeast-like white colonies were observed both on chromogenic media (CHROMagar, Becton Dickinson, USA), blood and chocolate agar after 24 hours of incubation at 36 °C. The species was then identified as Kluyveromyces marxianus by Matrix-Assisted Laser Desorption/Ionisation-Time of Flight (MALDI-TOF) mass spectrometry (MS) (Biomerieux Paris, France, VITEK MS database version 3.2) and finally confirmed via sequencing the internal transcribed spacer of the ribosomal DNA (ITS-rDNA). The ITS sequence of the isolate showed 100% identity with that of the ex-type strain of Kluyveromyces marxianus CBS 712 (GenBank accession number NR_111,251). The strain is deposited in the Jena Microbial Resource Collection (JMRC:NRZ:2921).
Immediate susceptibility testing was performed by VITEK 2 automated system (Biomerieux, Paris, France) using an AST-YS08 testing cartridge (acc. to CLSI). Additionally, Sensititre Yeast One YO10 microbroth dilution (acc. to CLSI) and a EUCAST broth microdilution were conducted (Table 1).Table 1 Kluyveromyces marxianus (syn.: Candida kefyr) susceptibility testing results after 24h. Antifungal agents: anidulafungin (AND), amphotericin B (AMB), micafungin (MIC), caspofungin (CAS), 5-flucytosine (5-FC), posaconazole (POS), voriconazole (VOR), itraconazole (IT), fluconazole (FLU).
Table 1Testing method Acc. to reference method Minimal inhibitory concentrations (MICs) of antifungal agent (μg/ml)
AND AMB MIC CAS 5-FC POS VOR IT FLU
VITEK 2 CLSI – 0.5 0.12 – – – ≤0.12 – 1
YO CLSI 0.12 1 0.12 0.12 ≤0.06 0.12 ≤0.06 0.12 0.5
Broth Microdilution EUCAST 0.03 0.125 – – – ≤0.016 ≤0.016 ≤0.016 0.5
A combination therapy of oral fluconazole (day 291 onwards: 400 mg daily loading dose; 200 mg daily maintenance dose) and hourly eye drops with voriconazole (1%) were begun followed by regular voriconazole (2%) injections. A total of four voriconazole injections were administered intracamerally, intrastromally and subconjunctivally (day 292, 294, 299, 301).
Unfortunately, the infiltrate remained refractory to this treatment, even after regimen was switched to amphotericin B (50 μg/ml in 0.1ml) injections (day 305). On day 306, emergency full thickness keratoplasty had to be performed, again followed by intracameral application of amphotericin B.
The explanted graft revealed a slightly discontinuous Descemet membrane, whereas the multilayered corneal epithelium showed no significant abnormalities. Histopathology confirmed Candida infection. Fungal structures (red arrows) were identified in both PAS and Grocott stain with surrounding mild inflammation (Fig. 1C).
After keratoplasty, the new graft showed no evidence of recurrence. As prophylaxis, antifungal therapy was continued with hourly application of topical voriconazole (1%) and two intracameral injections of amphotericin B (50 μg/ml in 0.1ml, day 319 and 322). For the remaining follow-up period up to day 354, findings were stable without signs of fungal activity, so that antimycotic topical and systemic therapy was discontinued.
3 Discussion
Yeast infection is a rare complication of DMEK, occurring in 0.15% of the cases [14]. In the majority, causative pathogens can be obtained from direct biopsy. However, recent studies indicate that Candida-positive cultures of the corneal donor rim (tissue left over from transplantation) may be a valuable parameter in predicting fungal keratitis prior to the onset of clinical symptoms [7]. However, our patient developed no evidence of infection even four weeks after surgery, and neither did the donor rim show any signs of infection and was therefore discarded. This procedure is supported by the fact that longer preservation time is not necessarily correlated with higher incidences of donor rim contamination. In fact, only a small fraction of cases with positive donor rim cultures develop post-keratoplasty infection [15]. Therefore, it remains debatable whether the patient would have benefited from a prolonged donor cornea conservation.
Kluyveromyces marxianus is a rare but severe and life-threatening cause of bloodstream infection, which is underlined by the fact that Kluyveromyces marxianus candidiasis is associated with a higher mortality in ICU patients compared to C. albicans [16]. Hematologic malignancies are considered as a risk factor. Interestingly, a seasonal peak of colonisation and infection is observed during summertime, which might be related to a lack of refrigeration in dairy products [13].
In our case the patient developed first symptoms of keratitis nine months after DMEK. Fontana et al. described onset of bacterial or fungal keratitis as late as four months after surgery [17]. The special localization of the yeast sequestered between graft and host cornea could influence the late onset of infection and makes it less accessible by topical or systemic therapy [7,9]. However, therapeutic approaches do exist combining systemic therapy with multiple intrastromal and intracameral antimycotic injections, avoiding full thickness keratoplasty in Candida lamellar infection [9].
Despite some Kluyveromyces marxianus in vitro data, no official breakpoints are established due to the paucity of clinical, pharmaceutical and epidemiological information [18]. Only EUCAST provides one fluconazole non-species related breakpoint for Candida based upon PK/PD data, which is defined as susceptible ≤2 μg/ml.
Our antifungal regimen included oral administration of fluconazole accompanied by intracameral and intrastromal injections of voriconazole, which was considered effective -at least in vitro- according to the susceptibility data (Table 1).
Previous case reports clearly indicate that intracorneal injections of voriconazole are useful alternatives challenging deep stromal Candida infections, especially when full thickness keratoplasty is clinically thought to be too invasive at that particular timepoint [19]. Voriconazole is reported effective against different Candida species in-vitro, but overall pharmacokinetic and pharmacodynamic data is limited. Even so, experimental studies suggest a demand of repeated drug administration at the site of infection, due the risk of accelerated loss of concentration below MIC of common fungi, which we met with multiple intracarmal and intrastromal injections [20]. Fluconazole was given as an attempt to further strengthen local azole concentrations, being aware that corneal drug penetrations of systemically added antifungals are usually poor.
Notably, comparing both EUCAST and CLSI methodologies performed on different testing devices (in-house broth microdilution versus semiautomatic- and automatic commercial broth microdilution), obtained minimum inhibitory concentrations (MICs) are in a similar range.
A change to amphotericin B was considered as a last attempt for medical treatment. It is debatable whether this change should have been considered earlier or even in first place, but it illustrates the dilemma of susceptibility testing in vitro and the concordant effect in vivo at the site of infection.
Nonetheless, graft removal was inevitable, underlining the complexity of treating this rare infection by constantly re-balancing the value of antifungal therapy with the lack of in vivo breakpoints against surgical measures, which will ultimately remove the infected focus but result in a new full thickness graft with a risk of reinfection and other complications.
Further interdisciplinary clinical studies and case reports are warranted not only to elucidate the role of Kluyveromyces marxianus as a rare pathogen but also to develop new treatment strategies for this challenging infection.
Funding source
The German National Reference Center NRZMyk is funded by the Robert Koch Institute from funds provided by the 10.13039/501100003107German Ministry of Health (grant no. 1369-240).
Consent
Written informed consent was obtained from the patient or legal guardian(s) for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Declaration of competing interest
There are none.
Acknowledgements
We thank Anastasia Besenfelder, Sabrina Mündlein for generating the susceptibility data and Ronny Martin, Yano Axel Pöhlmann for critically reviewing the manuscript. | HOURLY EYE DROPS (1%) | DrugDosageText | CC BY | 33665066 | 19,052,023 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal distension'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,006,800 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,006,800 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abortion spontaneous'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE CITRATE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,745,050 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ascites'. | Disseminated peritoneal coccidioidomycosis in pregnancy following fertility treatment: A case report and literature review.
Disseminated peritoneal coccidioidomycosis in the setting of early pregnancy after fertility treatment is rare and can present as a diagnostic challenge. A 39-year-old underwent ovarian stimulation with clomiphene citrate followed by HCG trigger and intrauterine insemination. She developed persistent abdominal pain, ascites and episodes of fever in early pregnancy, and eventually underwent a diagnostic laparoscopy for worsening clinical presentation. Operative findings were notable for peritoneal studding, infracolic omentum inflammation, bowel adhesions to the abdominal wall and normal-appearing uterus and adnexa. The pathology results indicated peritoneal Coccidioides immitis infection. Hormonal changes associated with fertility treatment and immune tolerance in pregnancy may increase the risk for disseminated peritoneal coccidioidomycosis. A high index of suspicion and a multidisciplinary team are important for the diagnostic workup and treatment plan of disseminated peritoneal coccidioidomycosis.
1 Introduction
Coccidioidomycosis is a fungal infection that results primarily in pulmonary disease and is endemic to the Southwest United States, Mexico and South America [1]. Extrapulmonary dissemination occurs in 1% of cases, usually in patients with risk factors like male sex, African ancestry, immunosuppression and pregnancy [[2], [3], [4]]. Prior data have shown that disseminated disease occurs in 23% of pregnant patients in the first trimester [5]. Extrapulmonary disease occurs most commonly in soft tissue, skin, joints and brain [6]. In contrast, peritoneum dissemination is rare, occurring through hematogenous spread or swallowing pulmonary secretions [7]. Disseminated cocciodiodes, like tuberculosis, is a great mimicker and can be challenging to diagnose. For example, early infection may present with persistently negative antibodies, especially in patients who are immunosuppressed or immune tolerant, as observed in pregnant women [3]. Additionally, there is a wide sensitivity and specificity of the enzyme immunoassay test, depending on lab assay [3].
To our knowledge, there are no reported cases of disseminated peritoneal coccidioidomycosis in the setting of early pregnancy following fertility treatment. We present the case of a 39-year-old woman with an early pregnancy resulting from ovarian stimulation with clomiphene citrate and intrauterine insemination who developed episodes of fever, ascites and abdominal pain ultimately requiring an exploratory laparotomy leading to a diagnosis of disseminated peritoneal Coccidioides immitis.
2 Case Presentation
A 39-year-old woman presented to an infertility clinic. She was diagnosed with unexplained secondary infertility associated with male factor. Her workup showed normal day 3 laboratory results (FSH 7.0 mIU/mL, estradiol 35 pg/mL), TSH 2.8 mcIU/mL, normal hysterosalpingogram, antral follicle count of 32 and semen analysis with mild oligoteratospermia. The couple had negative infectious disease screening, including hepatitis B and C, HIV, syphilis and HTLV 1–2. She underwent her first clomiphene citrate 50 mg cycle and developed two dominant follicles. Ovulation was triggered using 250 μg of HCG subcutaneously. She underwent an uncomplicated intrauterine insemination with 24 million fresh, motile washed sperm.
She began experiencing intermittent fevers and abdominal pain 8 days after insemination. She was seen by her primary care physician, who noted normal temperature, mild tenderness on exam and negative pregnancy test. She was counseled that her symptoms may be secondary to early pregnancy or mild gastritis. Three days later, she re-presented with a mild leukocytosis, serum beta-hCG 84 mIU/ml and normal electrolytes. Pelvic ultrasound showed moderate free fluid with echogenic debris, two left ovarian corpus lutea and an unremarkable appendix (Fig. 1). Consistent with early gestation, no pregnancy was identified, and suspected diagnosis was ruptured hemorrhagic cyst. However, her symptoms continued to worsen, with increasing ascites and distension, persistent fevers, mild increase in liver enzymes (AST 96 U/L, ALT 93 U/L]) and leukocytosis (15 K/uL), and she was sent to the emergency room at 4 weeks 1 day.Fig. 1 A. Large amount of free fluid in pouch of Douglas. B. Left ovary with corpus lutea.
Fig. 1
She had her first documented fever (38.2 °C), up-trending leukocytosis (17 K/uL), mild increase in liver enzymes (AST 50 U/L, ALT 80 U/L), beta-hCG of 127 mIU/ml, normal electrolytes and negative blood cultures. Abdominal ultrasound showed free fluid throughout the abdomen, thickened endometrial lining and a normal appendix. In addition to abdominal distension, the patient developed diarrhea and nausea. Given early gestation and goal to avoid CT radiation, a non-contrast MRI was performed, which showed significant free fluid, two ovarian cysts, likely corpus lutea, and inability to visualize the appendix. There was low suspicion for ovarian hyperstimulation syndrome given clomiphene citrate use for stimulation, two dominant follicles at trigger, normal electrolytes and absence of enlarged ovaries.
She was admitted for IV antibiotics for suspected bacterial peritonitis. Infectious disease was consulted. Ceftriaxone, flagyl and vancomycin were used for genitourinary coverage given fertility treatments. The patient was originally from Tanzania, which made the team suspicious for tuberculosis despite lack of clinical history and x-ray showing small pleural effusions.
By hospital day (HD) 3, she was clinically worsening, with fevers (39.4 °C), rising leukocytosis (23 K/uL) and abdominal distention. CT of the abdomen with contrast showed moderate ascites, omental nodularity and caking, not previously seen on MRI, concerning for malignancy or non-malignant causes, including tuberculosis. Gynecology oncology was consulted and the tumor markers CA-125, CA19-9, CEA, CA 15-3, CA 27.29, AFP were normal. Coccidioidomycosis IgM, IgG, and complement fixation titers were negative and <1:2 respectively. In terms of her pregnancy of unknown location, beta-HCGs were abnormally rising and trended every 48 h (126 mIU/ml, 180 mIU/ml, 395 mIU/ml).
On HD 5, paracentesis drained 800 l of fluid and interventional radiology-guided omental biopsies resulted in fat necrosis and granulomatous inflammation. Both peritoneal fluid and tissue biopsies were negative for neoplastic cells, CEA, acid-fast bacilli, fungal, bacterial, non-tuberculosis mycobacterium DNA and Mycobacterium tuberculosis (MTB) PCR. The only pertinent test was an indeterminate serum quantiferon gold; however, peritoneal fluid adenosine deaminase and negative MTB PCR were not consistent with tuberculosis. With progressively worsening symptoms and lack of diagnosis, the decision was made to proceed with laparoscopy for tissue diagnosis. Given abnormally rising beta-HCGs, pregnancy was likely non-viable, thus she elected for termination.
She underwent a diagnostic laparoscopy, omentectomy, lysis of adhesions and suction curettage on HD 8 with gynecology oncology, given CT results concerning for malignancy. Laparoscopy was converted to mini laparotomy due to significant adhesions and inability to obtain adequate biopsies for tissue diagnosis. Operative findings included extensive studding of peritoneum, infracolic omentum inflammation, bowel adhesions to abdominal wall, normal-appearing uterus and adnexa with 3.5 l of ascites (Fig. 2). Curettage showed decidualized endometrium without chorionic villi or coccidiodes. Beta-HCG down-trended to zero post-operatively consistent with successful surgical abortion.Fig. 2 A. Bowel attached to abdominal wall upon entry. B. Laparoscopic view of uterus, adnexa and ascites. C. “Caked omentum”, pathologic specimen.
Fig. 2
Post-operatively her fevers continued despite antibiotics. Surgical omental biopsy cultures resulted as Coccidioides immitis on postoperative day 11. Her only notable travel history was to Palm Springs, California, and visiting construction sites in the past two years, locations known to harbor coccidioidomycosis. After significant improvement on oral antifungal therapy, she was discharged on HD 15 with fluconazole 400 mg daily. She was followed by the multidisciplinary team as an outpatient. Coccidioides antibody complement fixation (titer 1:4) turned positive one month after her admission date.
3 Discussion
This is a unique case describing disseminated peritoneal coccidioidomycosis in a newly pregnant patient following fertility treatment with insemination. Peritoneal coccidioidomycosis is a challenging diagnosis as there are only 34 published cases [8]. Most patients with isolated peritoneal involvement and negative serology titers are immunosuppressed patients [3,9]. It is therefore possible that our pregnant patient had falsely negative titers due to the immune tolerance of pregnancy.
Most patients with disseminated coccidioidomycosis present gradually with abdominal distension and ascites occurring months to years after infection [2]. In our patient's case, it is possible that the immune-tolerance effects of pregnancy or the hormonal effects of ovarian stimulation may have contributed to her acute presentation. Prior data report pregnant women experience disseminated disease 100 times more frequently [2,6].
Our case highlights a possible association between hormonal changes with fertility treatment, immune tolerance in pregnancy, and risk for peritoneal coccidioidomycosis. Studies show that elevated serum levels of 17-beta-estradiol and progesterone in vitro increase coccidioidomycosis growth, contributing to dissemination [10]. Our patient received clomiphene citrate and was newly pregnant, thereby raising estradiol and progesterone levels. From an immunologic standpoint, pregnancy is a state of decreased cell-mediated immunity, which explains why coccidioidomycosis disseminates more commonly in pregnancy [4,11]. Evidence shows that pregnancy increases the risk of dissemination in proportion to gestational age, with greatest risk in the third trimester, thus our patient's presentation in early gestation was unusual [4,11]. In addition to pregnancy and presumably elevated hormones levels, African ancestry is another risk factor for disseminated disease in our case [11].
The timing and source of initial infection in our patient is unclear. Coccidioidomycosis was likely contracted years prior to presentation through environmental exposure. Even in dissemination, the usual source of initial infection is the pulmonary tract [1]. It is unusual for disseminated disease to involve the female genital tract, thus the insemination procedure or specimen are unlikely to be a cause for initial infection [12]. In concordance, endometrial tissue was negative for coccidioidomycosis. In the only other report of disseminated coccidioidomycosis in a woman who underwent ovarian stimulation with clomiphene citrate and insemination, presentation was several years after fertility treatment [10].
There is limited evidence on how to treat isolated peritoneal coccidioidomycosis. Management is typically fluconazole 400 mg daily for 6–12 months with duration guided by clinical, laboratory, and radiographic response [3]. Unlike other sites of dissemination, mortality is rare with isolated peritoneal coccidioidomycosis [13]. Going forward, our patient may have a small but increased risk of disease reactivation in future pregnancies. There is a lack of literature guiding reproductive patients for timing and risk of future conception [6,14]. According to the Infectious Disease Society of America guidelines, risk of reactivation in pregnancy is low in women who have completed therapy [3]. Once pregnant, the current recommendation is coccidioidal serologic testing every 6–12 weeks [3].
4 Conclusion
We believe this is the only published case of isolated peritoneal coccidioidomycosis in early pregnancy. The diagnosis of peritoneal coccidioidomycosis was particularly challenging given our patient's negative infectious workup and granulomatous tissue on initial omental biopsy. This case demonstrates the importance of a multidisciplinary team. Our patient was originally from Tanzania, which prompted us to consider tuberculosis as the etiology of her disease. Ultimately, local factors like living in California, rather than global factors, were the cause of her disease.
Contributors
Abigail Armstrong contributed to conception/design and drafting of the article.
Mika Watanabe contributed to conception/design and editing of the article.
Debika Bhattacharya was the infectious disease physician on the case and contributed to review and revision of the manuscript.
Mae Zakhour performed the surgery and contributed to review and revision of the manuscript.
Lindsay Kroener was the reproductive endocrinologist on the case and contributed to review and revision of the manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Obtained.
Provenance and Peer Review
This case report was peer reviewed. | CEFTRIAXONE, CLOMIPHENE, GONADOTROPHIN, CHORIONIC, METRONIDAZOLE\METRONIDAZOLE HYDROCHLORIDE, VANCOMYCIN | DrugsGivenReaction | CC BY | 33665141 | 19,006,800 | 2021-04 |
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