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What was the dosage of drug 'MYCOPHENOLATE MOFETIL'? | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | UNK UNK, UNKNOWN FREQ. | DrugDosageText | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
What was the dosage of drug 'TACROLIMUS'? | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | UNK UNK, UNKNOWN FREQ. | DrugDosageText | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
What was the outcome of reaction 'Systemic mycosis'? | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | Fatal | ReactionOutcome | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus viraemia'. | From TTP to Glomerulonephritis: A Lifetime of Lupus.
We report the case of a 56-year-old male patient, who over two decades, sequentially presented with a combination of clinical manifestations. These included thrombotic thrombocytopenic purpura (TTP), right leg deep vein thrombosis (DVT), and eventually constitutional symptoms, arthralgia, diffuse lymphadenopathy, pancytopenia, skin rash, pericarditis, and glomerulonephritis. Serologic tests and renal pathology uncovered a diagnosis of systemic lupus erythematosus (SLE), and immunosuppressive therapy was initiated. Soon after, the patient developed striking cytomegalovirus (CMV) viremia, requiring prolonged antiviral therapy and reduction of immunosuppression. Finally, an acute embolic stroke complicated the disease course. Prompt interventions allowed an excellent clinical outcome.
1. Introduction
Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, characterized by a wide spectrum of clinical manifestations, often exhibiting a relapsing-remitting course [1]. As treatment is based on immunosuppressive therapy, infections pose a major iatrogenic complication [2]. Here, we report a unique case of a middle-aged male, gradually presenting with a diverse constellation of systemic manifestations over a prolonged period. We discuss the clinical presentation, diagnostic implications, therapeutic decisions, and treatment complications.
2. Case Presentation
A 56-year-old male presented to the emergency department with a 2-month history of extreme weakness, fatigue, and anorexia. His past medical record was remarkable for a previous event of thrombotic thrombocytopenic purpura (TTP) 20 years earlier. He was then treated with plasmapheresis, aspirin, and corticosteroids, with complete recovery. 18 months thereafter, he was diagnosed with an unprovoked right leg deep vein thrombosis (DVT), for which no etiology was found. Noticeably, antiphospholipid antibodies (APLAs) were negative.
Similar constitutional symptoms had plagued the patient before. Several years prior to his current presentation, he was admitted for weakness and weight loss (30 kg over a few months). He then underwent a thorough investigation, including blood tests, whole-body computed tomography (CT), and positron emission tomography/CT (PET/CT). Diffuse hypermetabolic lymphadenopathy, involving axillary, abdominal, and retroperitoneal lymph nodes (LNs), was seen. Excisional biopsy of a pelvic LN (PN) and bone marrow (BM) biopsy were performed, both being unremarkable. Immune serologies sent at that time showed only a weakly positive antinuclear antibody (ANA). The differential diagnosis comprised a systemic infection, an indolent neoplastic process, and autoimmune lymphoproliferative syndrome (ALPS). None of these entities was proven however, leaving the patient undiagnosed despite regular follow-up. Thereafter, he spontaneously recovered, enjoying several uneventful years.
Upon the patient's current admission, physical examination revealed mild bilateral leg edema and numerous lichen-like skin lesions (see Figure 1). Recurrent fever spikes of up to 39°C were recorded, with otherwise normal vital signs. Blood tests were extremely abnormal, showing pancytopenia, hypoalbuminemia, high creatinine levels, and elevated inflammatory markers (see Table 1). While whole-body CT displayed no noteworthy findings, PET/CT demonstrated widespread hypermetabolic lymphadenopathy and diffusely increased BM uptake. BM and groin LN biopsies were performed, again being noncontributory. Peripheral blood flow cytometry, however, showed a high proportion (7%) of double-negative (DN) T cells (negative for both CD4+ and CD8+). Blood cultures and broad bacterial and viral serologies were negative. The patient's urinalysis was significant for hematuria and proteinuria, and urine microscopy revealed red blood cell (RBC) casts, along with dysmorphic RBCs. 24-hour urine collection demonstrated nephrotic range proteinuria (3.9 g/d).
During this time, the patient's clinical condition was one of the ongoing weakness, fatigue, and dyspnea. He also suffered from pleuritic chest pain and progressive, asymmetric leg edema. Further work-up directed at these complaints showed an extensive right leg DVT, elevated cardiac enzymes, and new-onset atrial fibrillation (AF). In addition, a small pericardial effusion was found on transesophageal echocardiography (TTE). Therapy with enoxaparin was started for his DVT and AF, and broad-spectrum antibiotic coverage was instituted for a suspected bacterial infection. Pericarditis was added to this ever-growing list of diagnoses.
Results of ANA and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody were reported at this stage, both being strongly positive, along with low complement levels (see Table 2). Notably, APLAs were negative. In light of the patient's deteriorating renal function and active urinary sediment, kidney biopsy was performed. Lupus nephritis stages 3 and 5 (focal proliferative and membranous glomerulonephritis, respectively) were present on pathology. Biopsy of the skin lesions demonstrated immune complex (lupus band) deposition and a lichen planus-like pathological picture. The patient was thus diagnosed with SLE and started on high-dose corticosteroid therapy, hydroxychloroquine, mycophenolate mofetil, and ramipril, with impressive clinical and laboratory improvement. After a 4-week hospital stay, he was eventually discharged for follow-up at the rheumatology and nephrology outpatient clinics.
Less than one month after discharge, the patient was readmitted due to a painful right calf ulcer, productive cough, and general weakness. Thorough work-up revealed significant cytomegalovirus (CMV) viremia (>925,000 copies/mL), with no signs of visceral involvement upon bronchoscopy, sigmoidoscopy, and ophthalmologic evaluation. The leg ulcer was attributed to postphlebitic syndrome, and biopsy of the ulcer was noncontributory. Cultures from both the ulcer and bronchoalveolar lavage fluid grew Pseudomonas aeroguinosa, and therapy with ciprofloxacin was started. Besides, mycophenolate mofetil and prednisone doses were reduced in an attempt to minimize immunosuppression, and intravenous ganciclovir therapy was initiated. The lack of clear signs of end-organ involvement has made it difficult to define the required duration of ganciclovir treatment, and the CMV viremia was monitored instead. Following the gradual elimination of viremia, antiviral therapy was stopped. Diligent wound care, compression stockings, and antibiotic treatment allowed stepwise healing of the ulcer.
Three months later, the patient was again admitted for sudden-onset dysarthria and right-sided hemiparesis. Brain CT angiography showed left middle cerebral artery branch obstruction, consistent with an embolic etiology. An emergent thrombectomy was performed. TTE, transesophageal echocardiography (TEE), and carotid Doppler studies revealed no embolic source. Aspirin and high-dose statin were added, and the patient continued apixaban. Gradually, he was able to regain excellent functional capacity.
As of today, one year after his index presentation, the patient is well and suffers no residual neurologic deficits. His most recent labs, including blood counts, chemistry panels, complement levels, and urinalysis, are unremarkable. His proteinuria has declined to 170 mg/d, and CMV titers in blood are undetectable.
3. Discussion
Our patient was eventually diagnosed with SLE. Over 20 years, he presented with an assembly of disease manifestations, including hematologic, musculoskeletal, dermatologic, cardiac, and renal phenomena. Initially experiencing events of TTP and DVT, he went on to develop, over many years and in a relapsing-remitting manner, constitutional symptoms, arthralgia, lymphadenopathy, pancytopenia, skin lesions, pericarditis, and glomerulonephritis. Past immune serologies showed only a weakly positive ANA, with normal complement levels. The absence of classic lupus manifestations in the past obscured the diagnosis, and it was not until significant visceral involvement occurred many years thereafter, that the correct conclusions were drawn. In these days of extensive testing and follow-up, “the great pretender,” lupus, appears to present a lesser diagnostic dilemma than in the past. Atypical manifestations, combined with spontaneous disease remissions, may nonetheless obfuscate the clinical picture.
Constitutional symptoms, including fatigue, anorexia, fever, and weight loss, are commonly seen in patients with SLE. Fatigue is a frequent, sometimes disabling, disease symptom. Its etiology is multifactorial and includes chronic inflammation, cytokine dysregulation, side effect of medications, comorbidities, and hormonal imbalances [3]. Fever occurs in 42–86% of SLE patients [4]. Its work-up can be challenging, and the disease occasionally presents as fever of unknown origin (FUO) [5].
SLE is known to have myriad hematologic manifestations, many of which appeared in our case. Lymphadenopathy is a common, often unappreciated feature. LNs are usually soft and nontender and may fluctuate in size with disease exacerbations. Biopsy usually shows reactive hyperplasia [6]. 50% of patients with SLE develop anemia, usually due to chronic inflammation and iron deficiency, and less often due to autoimmune hemolysis [7]. White blood cell abnormalities are also common in lupus and include leukopenia, lymphopenia, and neutropenia [8]. Thrombocytopenia, when related to active disease, tends to be lower than 50,000/mm3 and usually necessitates aggressive therapy [9]. While TTP may be a rare manifestation of SLE, it is seldom the presenting feature [10]. Thrombosis, on the contrary, is a well-known finding in the disease and is multifactorial. Despite APLAs being the most important risk factor, 40% of SLE patients negative for these antibodies will still experience a thrombotic event. Other factors that contribute to thrombosis in lupus include inflammatory disease activity, medications, and traditional risk factors (including smoking, diabetes, and hypertension) [11]. Immunologically, it is noteworthy that SLE patients may have increased numbers of DN T cells in peripheral blood, probably driven by excessive T cell stimulation. These cells synthesize interleukins and can stimulate B cells, contributing to the pathogenesis of kidney damage, for instance [12].
Regarding cardiac involvement, SLE can affect any layer of the heart. Pericardial effusion secondary to pericarditis is the most common manifestation [13]. Valvular heart disease is also well known in SLE. Left-sided valvular thickening is the predominant finding, followed by valvular vegetations, regurgitation, and stenosis [14]. It is worth mentioning that, in Libman–Sacks endocarditis complicating SLE, the sterile valvular vegetations have a greater tendency to embolize than in infective endocarditis, thus predisposing to neuropsychiatric disease, including ischemic stroke [15]. The latter is twice as common in SLE patients as compared to the general population. Contributing factors include embolic events, comorbidities (such as antiphospholipid syndrome and hypertension), systemic inflammation, and treatment complications [16]. AF, present in our case, is also known to be more common in SLE patients and is associated with increased mortality [17].
Skin disease is a well-characterized feature of lupus. Chronic cutaneous lupus includes a lupus-lichen overlap entity [18]. In the majority of patients with systemic disease, immunofluorescence reveals deposits at the dermal-epidermal junction in normal non-sun-exposed skin and at sites of cutaneous lesions, the so-called lupus band test [19].
Renal involvement remains one of the most devastating manifestations of SLE, with increased morbidity and mortality. Despite advances in management, 10% of the patients still progress to renal insufficiency and end-stage renal disease [20].
Complications of immunosuppression are also represented in our case. CMV viremia dominated the clinical picture, necessitating reduction of immunosuppression and institution of prolonged intravenous antiviral therapy. The heavy immunosuppressive regimens used in systemic autoimmune diseases are known to predispose to opportunistic infections. These remain the most frequent cause of hospitalization, morbidity, and mortality in SLE patients. More than half of the infections are viral, the most common being herpes zoster [2]. No guidelines in the field of rheumatology advise in favor of prophylactic therapy against CMV upon heavy immunosuppression, as opposed to the recommendations in patients undergoing BM transplantation. In cases of symptomatic CMV disease, treatment involves both the minimization of immunosuppression and the institution of antiviral therapy, typically with oral valganciclovir or intravenous ganciclovir [21]. Duration of intravenous therapy is usually guided by the target organ, lacking in our patient.
We believe our case is educational in several aspects. First, the patient showed a remarkable mixture of systemic manifestations (see Figure 2), varying in severity, pattern, and timing, with the eventual diagnosis being made two decades after his initial presentation. Secondly, despite appropriate therapy, he went on to develop complications of the disease and its treatment, including DVT, AF, CMV viremia, and stroke. Finally, the correct utilization of the therapeutic armamentarium and the proper implementation of urgent interventions yielded an excellent outcome.
Acknowledgments
The authors thank Professor Y. Ilan and Doctor H. Peleg for their important contribution to the patient's care.
Abbreviations
AF:Atrial fibrillation
ALPS:Autoimmune lymphoproliferative syndrome
ANA:Antinuclear antibody
Anti-dsDNA:Anti-double-stranded deoxyribonucleic acid
BM:Bone marrow
C:Complement
CMV:Cytomegalovirus
CT:Computed tomography
CRP:C-reactive protein
DN:Double negative
DVT:Deep vein thrombosis
RBC:Red blood cell
ESR:Erythrocyte sedimentation rate
FUO:Fever of unknown origin
LN:Lymph node
PET:Positron emission tomography
SLE:Systemic lupus erythematous
TEE:Transesophageal echocardiography
TTE:Transthoracic echocardiography
TTP:Thrombotic thrombocytopenic purpura.
Data Availability
All data used to support our findings are included within the article, and any additional data will be provided by the corresponding author upon reasonable request.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Figure 1 Lichen planus-like lesions on the patient's back. On biopsy, the positive lupus band test was found, signifying immune complex deposition.
Figure 2 Timeline of events in the patient's course over 20 years. AF: atrial fibrillation; CMV: cytomegalovirus; DVT: deep vein thrombosis, TTP: thrombotic thrombocytopenic purpura.
Table 1 The patient's blood chemistry and counts upon admission.
Lab parameter Value
Creatinine (μmol/L) (62–115) 180
Albumin (g/L) (32–48) 19
Leukocytes (μL) (3,790–10,330) 1,100
Hemoglobin (g/dL) (13.9–17.7) 7.5
Platelets (μL) (166,000–389,000) 62,000
Neutrophils (μL) (1780–7,000) 500
Lymphocytes (μL) (1,070–3,120) 300
ESR (mm/hr) (1–20) 62
CRP (mg/dL) (0–0.5) 2.7
Haptoglobin (mg/dL) (3–200) 296
Normal range values appear in brackets. ESR: erythrocyte sedimentation rate; CRP: C-reactive protein.
Table 2 The patient's immune serologies, completed during his admission.
Lab parameter Value
ANA (0/4) 4/4
Anti-DNA (U/mL) (<25) >200
C3 (U/mL) (90–180) 35
C4 (mg/dL) (10–40) 4
Coombs test Positive
Normal range values appear in brackets. ANA: antinuclear antibodies; Anti-DNA: anti-deoxyribonucleic acid; Anti-dsDNA: anti-double-stranded deoxyribonucleic acid; C: complement. | ENOXAPARIN, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, RAMIPRIL | DrugsGivenReaction | CC BY | 33488735 | 20,220,475 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pseudomonas infection'. | From TTP to Glomerulonephritis: A Lifetime of Lupus.
We report the case of a 56-year-old male patient, who over two decades, sequentially presented with a combination of clinical manifestations. These included thrombotic thrombocytopenic purpura (TTP), right leg deep vein thrombosis (DVT), and eventually constitutional symptoms, arthralgia, diffuse lymphadenopathy, pancytopenia, skin rash, pericarditis, and glomerulonephritis. Serologic tests and renal pathology uncovered a diagnosis of systemic lupus erythematosus (SLE), and immunosuppressive therapy was initiated. Soon after, the patient developed striking cytomegalovirus (CMV) viremia, requiring prolonged antiviral therapy and reduction of immunosuppression. Finally, an acute embolic stroke complicated the disease course. Prompt interventions allowed an excellent clinical outcome.
1. Introduction
Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, characterized by a wide spectrum of clinical manifestations, often exhibiting a relapsing-remitting course [1]. As treatment is based on immunosuppressive therapy, infections pose a major iatrogenic complication [2]. Here, we report a unique case of a middle-aged male, gradually presenting with a diverse constellation of systemic manifestations over a prolonged period. We discuss the clinical presentation, diagnostic implications, therapeutic decisions, and treatment complications.
2. Case Presentation
A 56-year-old male presented to the emergency department with a 2-month history of extreme weakness, fatigue, and anorexia. His past medical record was remarkable for a previous event of thrombotic thrombocytopenic purpura (TTP) 20 years earlier. He was then treated with plasmapheresis, aspirin, and corticosteroids, with complete recovery. 18 months thereafter, he was diagnosed with an unprovoked right leg deep vein thrombosis (DVT), for which no etiology was found. Noticeably, antiphospholipid antibodies (APLAs) were negative.
Similar constitutional symptoms had plagued the patient before. Several years prior to his current presentation, he was admitted for weakness and weight loss (30 kg over a few months). He then underwent a thorough investigation, including blood tests, whole-body computed tomography (CT), and positron emission tomography/CT (PET/CT). Diffuse hypermetabolic lymphadenopathy, involving axillary, abdominal, and retroperitoneal lymph nodes (LNs), was seen. Excisional biopsy of a pelvic LN (PN) and bone marrow (BM) biopsy were performed, both being unremarkable. Immune serologies sent at that time showed only a weakly positive antinuclear antibody (ANA). The differential diagnosis comprised a systemic infection, an indolent neoplastic process, and autoimmune lymphoproliferative syndrome (ALPS). None of these entities was proven however, leaving the patient undiagnosed despite regular follow-up. Thereafter, he spontaneously recovered, enjoying several uneventful years.
Upon the patient's current admission, physical examination revealed mild bilateral leg edema and numerous lichen-like skin lesions (see Figure 1). Recurrent fever spikes of up to 39°C were recorded, with otherwise normal vital signs. Blood tests were extremely abnormal, showing pancytopenia, hypoalbuminemia, high creatinine levels, and elevated inflammatory markers (see Table 1). While whole-body CT displayed no noteworthy findings, PET/CT demonstrated widespread hypermetabolic lymphadenopathy and diffusely increased BM uptake. BM and groin LN biopsies were performed, again being noncontributory. Peripheral blood flow cytometry, however, showed a high proportion (7%) of double-negative (DN) T cells (negative for both CD4+ and CD8+). Blood cultures and broad bacterial and viral serologies were negative. The patient's urinalysis was significant for hematuria and proteinuria, and urine microscopy revealed red blood cell (RBC) casts, along with dysmorphic RBCs. 24-hour urine collection demonstrated nephrotic range proteinuria (3.9 g/d).
During this time, the patient's clinical condition was one of the ongoing weakness, fatigue, and dyspnea. He also suffered from pleuritic chest pain and progressive, asymmetric leg edema. Further work-up directed at these complaints showed an extensive right leg DVT, elevated cardiac enzymes, and new-onset atrial fibrillation (AF). In addition, a small pericardial effusion was found on transesophageal echocardiography (TTE). Therapy with enoxaparin was started for his DVT and AF, and broad-spectrum antibiotic coverage was instituted for a suspected bacterial infection. Pericarditis was added to this ever-growing list of diagnoses.
Results of ANA and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody were reported at this stage, both being strongly positive, along with low complement levels (see Table 2). Notably, APLAs were negative. In light of the patient's deteriorating renal function and active urinary sediment, kidney biopsy was performed. Lupus nephritis stages 3 and 5 (focal proliferative and membranous glomerulonephritis, respectively) were present on pathology. Biopsy of the skin lesions demonstrated immune complex (lupus band) deposition and a lichen planus-like pathological picture. The patient was thus diagnosed with SLE and started on high-dose corticosteroid therapy, hydroxychloroquine, mycophenolate mofetil, and ramipril, with impressive clinical and laboratory improvement. After a 4-week hospital stay, he was eventually discharged for follow-up at the rheumatology and nephrology outpatient clinics.
Less than one month after discharge, the patient was readmitted due to a painful right calf ulcer, productive cough, and general weakness. Thorough work-up revealed significant cytomegalovirus (CMV) viremia (>925,000 copies/mL), with no signs of visceral involvement upon bronchoscopy, sigmoidoscopy, and ophthalmologic evaluation. The leg ulcer was attributed to postphlebitic syndrome, and biopsy of the ulcer was noncontributory. Cultures from both the ulcer and bronchoalveolar lavage fluid grew Pseudomonas aeroguinosa, and therapy with ciprofloxacin was started. Besides, mycophenolate mofetil and prednisone doses were reduced in an attempt to minimize immunosuppression, and intravenous ganciclovir therapy was initiated. The lack of clear signs of end-organ involvement has made it difficult to define the required duration of ganciclovir treatment, and the CMV viremia was monitored instead. Following the gradual elimination of viremia, antiviral therapy was stopped. Diligent wound care, compression stockings, and antibiotic treatment allowed stepwise healing of the ulcer.
Three months later, the patient was again admitted for sudden-onset dysarthria and right-sided hemiparesis. Brain CT angiography showed left middle cerebral artery branch obstruction, consistent with an embolic etiology. An emergent thrombectomy was performed. TTE, transesophageal echocardiography (TEE), and carotid Doppler studies revealed no embolic source. Aspirin and high-dose statin were added, and the patient continued apixaban. Gradually, he was able to regain excellent functional capacity.
As of today, one year after his index presentation, the patient is well and suffers no residual neurologic deficits. His most recent labs, including blood counts, chemistry panels, complement levels, and urinalysis, are unremarkable. His proteinuria has declined to 170 mg/d, and CMV titers in blood are undetectable.
3. Discussion
Our patient was eventually diagnosed with SLE. Over 20 years, he presented with an assembly of disease manifestations, including hematologic, musculoskeletal, dermatologic, cardiac, and renal phenomena. Initially experiencing events of TTP and DVT, he went on to develop, over many years and in a relapsing-remitting manner, constitutional symptoms, arthralgia, lymphadenopathy, pancytopenia, skin lesions, pericarditis, and glomerulonephritis. Past immune serologies showed only a weakly positive ANA, with normal complement levels. The absence of classic lupus manifestations in the past obscured the diagnosis, and it was not until significant visceral involvement occurred many years thereafter, that the correct conclusions were drawn. In these days of extensive testing and follow-up, “the great pretender,” lupus, appears to present a lesser diagnostic dilemma than in the past. Atypical manifestations, combined with spontaneous disease remissions, may nonetheless obfuscate the clinical picture.
Constitutional symptoms, including fatigue, anorexia, fever, and weight loss, are commonly seen in patients with SLE. Fatigue is a frequent, sometimes disabling, disease symptom. Its etiology is multifactorial and includes chronic inflammation, cytokine dysregulation, side effect of medications, comorbidities, and hormonal imbalances [3]. Fever occurs in 42–86% of SLE patients [4]. Its work-up can be challenging, and the disease occasionally presents as fever of unknown origin (FUO) [5].
SLE is known to have myriad hematologic manifestations, many of which appeared in our case. Lymphadenopathy is a common, often unappreciated feature. LNs are usually soft and nontender and may fluctuate in size with disease exacerbations. Biopsy usually shows reactive hyperplasia [6]. 50% of patients with SLE develop anemia, usually due to chronic inflammation and iron deficiency, and less often due to autoimmune hemolysis [7]. White blood cell abnormalities are also common in lupus and include leukopenia, lymphopenia, and neutropenia [8]. Thrombocytopenia, when related to active disease, tends to be lower than 50,000/mm3 and usually necessitates aggressive therapy [9]. While TTP may be a rare manifestation of SLE, it is seldom the presenting feature [10]. Thrombosis, on the contrary, is a well-known finding in the disease and is multifactorial. Despite APLAs being the most important risk factor, 40% of SLE patients negative for these antibodies will still experience a thrombotic event. Other factors that contribute to thrombosis in lupus include inflammatory disease activity, medications, and traditional risk factors (including smoking, diabetes, and hypertension) [11]. Immunologically, it is noteworthy that SLE patients may have increased numbers of DN T cells in peripheral blood, probably driven by excessive T cell stimulation. These cells synthesize interleukins and can stimulate B cells, contributing to the pathogenesis of kidney damage, for instance [12].
Regarding cardiac involvement, SLE can affect any layer of the heart. Pericardial effusion secondary to pericarditis is the most common manifestation [13]. Valvular heart disease is also well known in SLE. Left-sided valvular thickening is the predominant finding, followed by valvular vegetations, regurgitation, and stenosis [14]. It is worth mentioning that, in Libman–Sacks endocarditis complicating SLE, the sterile valvular vegetations have a greater tendency to embolize than in infective endocarditis, thus predisposing to neuropsychiatric disease, including ischemic stroke [15]. The latter is twice as common in SLE patients as compared to the general population. Contributing factors include embolic events, comorbidities (such as antiphospholipid syndrome and hypertension), systemic inflammation, and treatment complications [16]. AF, present in our case, is also known to be more common in SLE patients and is associated with increased mortality [17].
Skin disease is a well-characterized feature of lupus. Chronic cutaneous lupus includes a lupus-lichen overlap entity [18]. In the majority of patients with systemic disease, immunofluorescence reveals deposits at the dermal-epidermal junction in normal non-sun-exposed skin and at sites of cutaneous lesions, the so-called lupus band test [19].
Renal involvement remains one of the most devastating manifestations of SLE, with increased morbidity and mortality. Despite advances in management, 10% of the patients still progress to renal insufficiency and end-stage renal disease [20].
Complications of immunosuppression are also represented in our case. CMV viremia dominated the clinical picture, necessitating reduction of immunosuppression and institution of prolonged intravenous antiviral therapy. The heavy immunosuppressive regimens used in systemic autoimmune diseases are known to predispose to opportunistic infections. These remain the most frequent cause of hospitalization, morbidity, and mortality in SLE patients. More than half of the infections are viral, the most common being herpes zoster [2]. No guidelines in the field of rheumatology advise in favor of prophylactic therapy against CMV upon heavy immunosuppression, as opposed to the recommendations in patients undergoing BM transplantation. In cases of symptomatic CMV disease, treatment involves both the minimization of immunosuppression and the institution of antiviral therapy, typically with oral valganciclovir or intravenous ganciclovir [21]. Duration of intravenous therapy is usually guided by the target organ, lacking in our patient.
We believe our case is educational in several aspects. First, the patient showed a remarkable mixture of systemic manifestations (see Figure 2), varying in severity, pattern, and timing, with the eventual diagnosis being made two decades after his initial presentation. Secondly, despite appropriate therapy, he went on to develop complications of the disease and its treatment, including DVT, AF, CMV viremia, and stroke. Finally, the correct utilization of the therapeutic armamentarium and the proper implementation of urgent interventions yielded an excellent outcome.
Acknowledgments
The authors thank Professor Y. Ilan and Doctor H. Peleg for their important contribution to the patient's care.
Abbreviations
AF:Atrial fibrillation
ALPS:Autoimmune lymphoproliferative syndrome
ANA:Antinuclear antibody
Anti-dsDNA:Anti-double-stranded deoxyribonucleic acid
BM:Bone marrow
C:Complement
CMV:Cytomegalovirus
CT:Computed tomography
CRP:C-reactive protein
DN:Double negative
DVT:Deep vein thrombosis
RBC:Red blood cell
ESR:Erythrocyte sedimentation rate
FUO:Fever of unknown origin
LN:Lymph node
PET:Positron emission tomography
SLE:Systemic lupus erythematous
TEE:Transesophageal echocardiography
TTE:Transthoracic echocardiography
TTP:Thrombotic thrombocytopenic purpura.
Data Availability
All data used to support our findings are included within the article, and any additional data will be provided by the corresponding author upon reasonable request.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Figure 1 Lichen planus-like lesions on the patient's back. On biopsy, the positive lupus band test was found, signifying immune complex deposition.
Figure 2 Timeline of events in the patient's course over 20 years. AF: atrial fibrillation; CMV: cytomegalovirus; DVT: deep vein thrombosis, TTP: thrombotic thrombocytopenic purpura.
Table 1 The patient's blood chemistry and counts upon admission.
Lab parameter Value
Creatinine (μmol/L) (62–115) 180
Albumin (g/L) (32–48) 19
Leukocytes (μL) (3,790–10,330) 1,100
Hemoglobin (g/dL) (13.9–17.7) 7.5
Platelets (μL) (166,000–389,000) 62,000
Neutrophils (μL) (1780–7,000) 500
Lymphocytes (μL) (1,070–3,120) 300
ESR (mm/hr) (1–20) 62
CRP (mg/dL) (0–0.5) 2.7
Haptoglobin (mg/dL) (3–200) 296
Normal range values appear in brackets. ESR: erythrocyte sedimentation rate; CRP: C-reactive protein.
Table 2 The patient's immune serologies, completed during his admission.
Lab parameter Value
ANA (0/4) 4/4
Anti-DNA (U/mL) (<25) >200
C3 (U/mL) (90–180) 35
C4 (mg/dL) (10–40) 4
Coombs test Positive
Normal range values appear in brackets. ANA: antinuclear antibodies; Anti-DNA: anti-deoxyribonucleic acid; Anti-dsDNA: anti-double-stranded deoxyribonucleic acid; C: complement. | ENOXAPARIN, HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, RAMIPRIL | DrugsGivenReaction | CC BY | 33488735 | 20,220,475 | 2021 |
What was the outcome of reaction 'Cytomegalovirus viraemia'? | From TTP to Glomerulonephritis: A Lifetime of Lupus.
We report the case of a 56-year-old male patient, who over two decades, sequentially presented with a combination of clinical manifestations. These included thrombotic thrombocytopenic purpura (TTP), right leg deep vein thrombosis (DVT), and eventually constitutional symptoms, arthralgia, diffuse lymphadenopathy, pancytopenia, skin rash, pericarditis, and glomerulonephritis. Serologic tests and renal pathology uncovered a diagnosis of systemic lupus erythematosus (SLE), and immunosuppressive therapy was initiated. Soon after, the patient developed striking cytomegalovirus (CMV) viremia, requiring prolonged antiviral therapy and reduction of immunosuppression. Finally, an acute embolic stroke complicated the disease course. Prompt interventions allowed an excellent clinical outcome.
1. Introduction
Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, characterized by a wide spectrum of clinical manifestations, often exhibiting a relapsing-remitting course [1]. As treatment is based on immunosuppressive therapy, infections pose a major iatrogenic complication [2]. Here, we report a unique case of a middle-aged male, gradually presenting with a diverse constellation of systemic manifestations over a prolonged period. We discuss the clinical presentation, diagnostic implications, therapeutic decisions, and treatment complications.
2. Case Presentation
A 56-year-old male presented to the emergency department with a 2-month history of extreme weakness, fatigue, and anorexia. His past medical record was remarkable for a previous event of thrombotic thrombocytopenic purpura (TTP) 20 years earlier. He was then treated with plasmapheresis, aspirin, and corticosteroids, with complete recovery. 18 months thereafter, he was diagnosed with an unprovoked right leg deep vein thrombosis (DVT), for which no etiology was found. Noticeably, antiphospholipid antibodies (APLAs) were negative.
Similar constitutional symptoms had plagued the patient before. Several years prior to his current presentation, he was admitted for weakness and weight loss (30 kg over a few months). He then underwent a thorough investigation, including blood tests, whole-body computed tomography (CT), and positron emission tomography/CT (PET/CT). Diffuse hypermetabolic lymphadenopathy, involving axillary, abdominal, and retroperitoneal lymph nodes (LNs), was seen. Excisional biopsy of a pelvic LN (PN) and bone marrow (BM) biopsy were performed, both being unremarkable. Immune serologies sent at that time showed only a weakly positive antinuclear antibody (ANA). The differential diagnosis comprised a systemic infection, an indolent neoplastic process, and autoimmune lymphoproliferative syndrome (ALPS). None of these entities was proven however, leaving the patient undiagnosed despite regular follow-up. Thereafter, he spontaneously recovered, enjoying several uneventful years.
Upon the patient's current admission, physical examination revealed mild bilateral leg edema and numerous lichen-like skin lesions (see Figure 1). Recurrent fever spikes of up to 39°C were recorded, with otherwise normal vital signs. Blood tests were extremely abnormal, showing pancytopenia, hypoalbuminemia, high creatinine levels, and elevated inflammatory markers (see Table 1). While whole-body CT displayed no noteworthy findings, PET/CT demonstrated widespread hypermetabolic lymphadenopathy and diffusely increased BM uptake. BM and groin LN biopsies were performed, again being noncontributory. Peripheral blood flow cytometry, however, showed a high proportion (7%) of double-negative (DN) T cells (negative for both CD4+ and CD8+). Blood cultures and broad bacterial and viral serologies were negative. The patient's urinalysis was significant for hematuria and proteinuria, and urine microscopy revealed red blood cell (RBC) casts, along with dysmorphic RBCs. 24-hour urine collection demonstrated nephrotic range proteinuria (3.9 g/d).
During this time, the patient's clinical condition was one of the ongoing weakness, fatigue, and dyspnea. He also suffered from pleuritic chest pain and progressive, asymmetric leg edema. Further work-up directed at these complaints showed an extensive right leg DVT, elevated cardiac enzymes, and new-onset atrial fibrillation (AF). In addition, a small pericardial effusion was found on transesophageal echocardiography (TTE). Therapy with enoxaparin was started for his DVT and AF, and broad-spectrum antibiotic coverage was instituted for a suspected bacterial infection. Pericarditis was added to this ever-growing list of diagnoses.
Results of ANA and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody were reported at this stage, both being strongly positive, along with low complement levels (see Table 2). Notably, APLAs were negative. In light of the patient's deteriorating renal function and active urinary sediment, kidney biopsy was performed. Lupus nephritis stages 3 and 5 (focal proliferative and membranous glomerulonephritis, respectively) were present on pathology. Biopsy of the skin lesions demonstrated immune complex (lupus band) deposition and a lichen planus-like pathological picture. The patient was thus diagnosed with SLE and started on high-dose corticosteroid therapy, hydroxychloroquine, mycophenolate mofetil, and ramipril, with impressive clinical and laboratory improvement. After a 4-week hospital stay, he was eventually discharged for follow-up at the rheumatology and nephrology outpatient clinics.
Less than one month after discharge, the patient was readmitted due to a painful right calf ulcer, productive cough, and general weakness. Thorough work-up revealed significant cytomegalovirus (CMV) viremia (>925,000 copies/mL), with no signs of visceral involvement upon bronchoscopy, sigmoidoscopy, and ophthalmologic evaluation. The leg ulcer was attributed to postphlebitic syndrome, and biopsy of the ulcer was noncontributory. Cultures from both the ulcer and bronchoalveolar lavage fluid grew Pseudomonas aeroguinosa, and therapy with ciprofloxacin was started. Besides, mycophenolate mofetil and prednisone doses were reduced in an attempt to minimize immunosuppression, and intravenous ganciclovir therapy was initiated. The lack of clear signs of end-organ involvement has made it difficult to define the required duration of ganciclovir treatment, and the CMV viremia was monitored instead. Following the gradual elimination of viremia, antiviral therapy was stopped. Diligent wound care, compression stockings, and antibiotic treatment allowed stepwise healing of the ulcer.
Three months later, the patient was again admitted for sudden-onset dysarthria and right-sided hemiparesis. Brain CT angiography showed left middle cerebral artery branch obstruction, consistent with an embolic etiology. An emergent thrombectomy was performed. TTE, transesophageal echocardiography (TEE), and carotid Doppler studies revealed no embolic source. Aspirin and high-dose statin were added, and the patient continued apixaban. Gradually, he was able to regain excellent functional capacity.
As of today, one year after his index presentation, the patient is well and suffers no residual neurologic deficits. His most recent labs, including blood counts, chemistry panels, complement levels, and urinalysis, are unremarkable. His proteinuria has declined to 170 mg/d, and CMV titers in blood are undetectable.
3. Discussion
Our patient was eventually diagnosed with SLE. Over 20 years, he presented with an assembly of disease manifestations, including hematologic, musculoskeletal, dermatologic, cardiac, and renal phenomena. Initially experiencing events of TTP and DVT, he went on to develop, over many years and in a relapsing-remitting manner, constitutional symptoms, arthralgia, lymphadenopathy, pancytopenia, skin lesions, pericarditis, and glomerulonephritis. Past immune serologies showed only a weakly positive ANA, with normal complement levels. The absence of classic lupus manifestations in the past obscured the diagnosis, and it was not until significant visceral involvement occurred many years thereafter, that the correct conclusions were drawn. In these days of extensive testing and follow-up, “the great pretender,” lupus, appears to present a lesser diagnostic dilemma than in the past. Atypical manifestations, combined with spontaneous disease remissions, may nonetheless obfuscate the clinical picture.
Constitutional symptoms, including fatigue, anorexia, fever, and weight loss, are commonly seen in patients with SLE. Fatigue is a frequent, sometimes disabling, disease symptom. Its etiology is multifactorial and includes chronic inflammation, cytokine dysregulation, side effect of medications, comorbidities, and hormonal imbalances [3]. Fever occurs in 42–86% of SLE patients [4]. Its work-up can be challenging, and the disease occasionally presents as fever of unknown origin (FUO) [5].
SLE is known to have myriad hematologic manifestations, many of which appeared in our case. Lymphadenopathy is a common, often unappreciated feature. LNs are usually soft and nontender and may fluctuate in size with disease exacerbations. Biopsy usually shows reactive hyperplasia [6]. 50% of patients with SLE develop anemia, usually due to chronic inflammation and iron deficiency, and less often due to autoimmune hemolysis [7]. White blood cell abnormalities are also common in lupus and include leukopenia, lymphopenia, and neutropenia [8]. Thrombocytopenia, when related to active disease, tends to be lower than 50,000/mm3 and usually necessitates aggressive therapy [9]. While TTP may be a rare manifestation of SLE, it is seldom the presenting feature [10]. Thrombosis, on the contrary, is a well-known finding in the disease and is multifactorial. Despite APLAs being the most important risk factor, 40% of SLE patients negative for these antibodies will still experience a thrombotic event. Other factors that contribute to thrombosis in lupus include inflammatory disease activity, medications, and traditional risk factors (including smoking, diabetes, and hypertension) [11]. Immunologically, it is noteworthy that SLE patients may have increased numbers of DN T cells in peripheral blood, probably driven by excessive T cell stimulation. These cells synthesize interleukins and can stimulate B cells, contributing to the pathogenesis of kidney damage, for instance [12].
Regarding cardiac involvement, SLE can affect any layer of the heart. Pericardial effusion secondary to pericarditis is the most common manifestation [13]. Valvular heart disease is also well known in SLE. Left-sided valvular thickening is the predominant finding, followed by valvular vegetations, regurgitation, and stenosis [14]. It is worth mentioning that, in Libman–Sacks endocarditis complicating SLE, the sterile valvular vegetations have a greater tendency to embolize than in infective endocarditis, thus predisposing to neuropsychiatric disease, including ischemic stroke [15]. The latter is twice as common in SLE patients as compared to the general population. Contributing factors include embolic events, comorbidities (such as antiphospholipid syndrome and hypertension), systemic inflammation, and treatment complications [16]. AF, present in our case, is also known to be more common in SLE patients and is associated with increased mortality [17].
Skin disease is a well-characterized feature of lupus. Chronic cutaneous lupus includes a lupus-lichen overlap entity [18]. In the majority of patients with systemic disease, immunofluorescence reveals deposits at the dermal-epidermal junction in normal non-sun-exposed skin and at sites of cutaneous lesions, the so-called lupus band test [19].
Renal involvement remains one of the most devastating manifestations of SLE, with increased morbidity and mortality. Despite advances in management, 10% of the patients still progress to renal insufficiency and end-stage renal disease [20].
Complications of immunosuppression are also represented in our case. CMV viremia dominated the clinical picture, necessitating reduction of immunosuppression and institution of prolonged intravenous antiviral therapy. The heavy immunosuppressive regimens used in systemic autoimmune diseases are known to predispose to opportunistic infections. These remain the most frequent cause of hospitalization, morbidity, and mortality in SLE patients. More than half of the infections are viral, the most common being herpes zoster [2]. No guidelines in the field of rheumatology advise in favor of prophylactic therapy against CMV upon heavy immunosuppression, as opposed to the recommendations in patients undergoing BM transplantation. In cases of symptomatic CMV disease, treatment involves both the minimization of immunosuppression and the institution of antiviral therapy, typically with oral valganciclovir or intravenous ganciclovir [21]. Duration of intravenous therapy is usually guided by the target organ, lacking in our patient.
We believe our case is educational in several aspects. First, the patient showed a remarkable mixture of systemic manifestations (see Figure 2), varying in severity, pattern, and timing, with the eventual diagnosis being made two decades after his initial presentation. Secondly, despite appropriate therapy, he went on to develop complications of the disease and its treatment, including DVT, AF, CMV viremia, and stroke. Finally, the correct utilization of the therapeutic armamentarium and the proper implementation of urgent interventions yielded an excellent outcome.
Acknowledgments
The authors thank Professor Y. Ilan and Doctor H. Peleg for their important contribution to the patient's care.
Abbreviations
AF:Atrial fibrillation
ALPS:Autoimmune lymphoproliferative syndrome
ANA:Antinuclear antibody
Anti-dsDNA:Anti-double-stranded deoxyribonucleic acid
BM:Bone marrow
C:Complement
CMV:Cytomegalovirus
CT:Computed tomography
CRP:C-reactive protein
DN:Double negative
DVT:Deep vein thrombosis
RBC:Red blood cell
ESR:Erythrocyte sedimentation rate
FUO:Fever of unknown origin
LN:Lymph node
PET:Positron emission tomography
SLE:Systemic lupus erythematous
TEE:Transesophageal echocardiography
TTE:Transthoracic echocardiography
TTP:Thrombotic thrombocytopenic purpura.
Data Availability
All data used to support our findings are included within the article, and any additional data will be provided by the corresponding author upon reasonable request.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Figure 1 Lichen planus-like lesions on the patient's back. On biopsy, the positive lupus band test was found, signifying immune complex deposition.
Figure 2 Timeline of events in the patient's course over 20 years. AF: atrial fibrillation; CMV: cytomegalovirus; DVT: deep vein thrombosis, TTP: thrombotic thrombocytopenic purpura.
Table 1 The patient's blood chemistry and counts upon admission.
Lab parameter Value
Creatinine (μmol/L) (62–115) 180
Albumin (g/L) (32–48) 19
Leukocytes (μL) (3,790–10,330) 1,100
Hemoglobin (g/dL) (13.9–17.7) 7.5
Platelets (μL) (166,000–389,000) 62,000
Neutrophils (μL) (1780–7,000) 500
Lymphocytes (μL) (1,070–3,120) 300
ESR (mm/hr) (1–20) 62
CRP (mg/dL) (0–0.5) 2.7
Haptoglobin (mg/dL) (3–200) 296
Normal range values appear in brackets. ESR: erythrocyte sedimentation rate; CRP: C-reactive protein.
Table 2 The patient's immune serologies, completed during his admission.
Lab parameter Value
ANA (0/4) 4/4
Anti-DNA (U/mL) (<25) >200
C3 (U/mL) (90–180) 35
C4 (mg/dL) (10–40) 4
Coombs test Positive
Normal range values appear in brackets. ANA: antinuclear antibodies; Anti-DNA: anti-deoxyribonucleic acid; Anti-dsDNA: anti-double-stranded deoxyribonucleic acid; C: complement. | Recovered | ReactionOutcome | CC BY | 33488735 | 20,220,475 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Agitation'. | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | INFLIXIMAB, MESALAMINE, PROBIOTICS NOS | DrugsGivenReaction | CC BY | 33489084 | 18,863,547 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bone marrow failure'. | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | INFLIXIMAB, MESALAMINE, PROBIOTICS NOS | DrugsGivenReaction | CC BY | 33489084 | 18,863,547 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disseminated tuberculosis'. | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | INFLIXIMAB, MESALAMINE, PROBIOTICS NOS | DrugsGivenReaction | CC BY | 33489084 | 18,863,547 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Meningitis tuberculous'. | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | HYDROCORTISONE, MESALAMINE, VEDOLIZUMAB | DrugsGivenReaction | CC BY | 33489084 | 19,002,770 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Psychotic symptom'. | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | INFLIXIMAB, MESALAMINE, PROBIOTICS NOS | DrugsGivenReaction | CC BY | 33489084 | 18,863,547 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tuberculoma of central nervous system'. | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | HYDROCORTISONE, MESALAMINE, VEDOLIZUMAB | DrugsGivenReaction | CC BY | 33489084 | 19,002,770 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tuberculous pleurisy'. | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | HYDROCORTISONE, MESALAMINE, VEDOLIZUMAB | DrugsGivenReaction | CC BY | 33489084 | 19,002,770 | 2021 |
What was the administration route of drug 'INFLIXIMAB'? | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33489084 | 18,863,547 | 2021 |
What was the dosage of drug 'INFLIXIMAB'? | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | UNKNOWN | DrugDosageText | CC BY | 33489084 | 18,863,547 | 2021 |
What was the dosage of drug 'MESALAMINE'? | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | UNKNOWN | DrugDosageText | CC BY | 33489084 | 18,863,547 | 2021 |
What was the dosage of drug 'PROBIOTICS NOS'? | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | UNKNOWN | DrugDosageText | CC BY | 33489084 | 18,863,547 | 2021 |
What was the outcome of reaction 'Disseminated tuberculosis'? | Various Forms of Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents.
Although there are undeniable advantages of treatment of the inflammatory bowel diseases, Crohn's disease, and ulcerative colitis, with biological agents, the increased susceptibility to tuberculosis should not be ignored. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. Primary tuberculosis is uncommon in the setting of inflammatory bowel disease: reactivation of latent tuberculosis is of greater concern. Consequently, latent infection should be excluded in patients who qualify for immunosuppressive treatments. Apart from the review of the literature, this article also presents three cases of different patterns of tuberculosis that occurred during treatment with infliximab, adalimumab, or vedolizumab. The first case reports a case of tuberculosis presenting as right middle lobe pneumonia. The second case featured miliary tuberculosis of the lungs with involvement of the mediastinal lymph nodes, liver, and spleen. The third patient developed a tuberculoma of the right parietal lobe and tuberculous meningitis. It is important to reiterate that every patient qualifying for a biologic agent should undergo testing to accurately identify latent tuberculosis, as well as precise monitoring for the possible development of one of the various forms or patterns of tuberculosis during treatment.
1. Introduction
It is well known that treatment with biological agents for various medical conditions for many patients was revolutionary and provided a real chance for positive shift in the course and prognosis of the underlying disease. Biotherapies have become applicable not only in the treatment of inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) but also in the treatment of such conditions as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [1] and in therapy of dermatological diseases such as plaque psoriasis [2] and hidradenitis suppurativa (HS) [3]. These biotherapies have also been evaluated in pulmonary diseases such as asthma, but, despite promising results from preclinical studies, they have proved to be ineffective [4].
In spite of the unquestionable benefits of these biotherapies, particularly in difficult-to-treat cases of IBD, it is important to not overlook the fact that, in some cases, biological treatments may lead to serious adverse reactions. One example is the reactivation of latent infection with Mycobacterium tuberculosis or new-onset tuberculosis (TB).
Although both CD and UC share features of uncontrolled and relapsing inflammation, they can differ in terms of clinical features, etiology, and treatment. In 5% to 15% of cases (more often among children), it is not possible to differentiate based on the endoscopic or histological examination; in such situations, the term inflammatory bowel disease unclassified (IBDU) is used to describe the condition [5].
CD is an inflammatory, autoimmune-related disease of unclear etiology, which may involve each part of the gastrointestinal tract, especially the small intestine. The disease is characterized by full-thickness, segmental changes with the presence of noncaseating granulomas; it can be complicated by the development of abscesses, fistulae, or perianal changes. In patients with CD, parenteral symptoms are often observed (affecting the skin, choroid, joints, liver, and bile ducts). Moreover, patients have a higher risk of developing colorectal cancer [6].
The first-line agents in the treatment of CD are often corticosteroids in combination, in case of extensive involvement of the small intestine, with steroid-sparing immunosuppressive medications such as azathioprine, mercaptopurine, and methotrexate. In case of infection or the presence of fistulae, antibiotics such as ciprofloxacin and metronidazole and, subsequently, biological agents are also used [6].
UC is characterized by continuous inflammatory changes typically extending from the rectum, with involvement limited to the large bowel. In contrast to CD, in UC, the inflammation is limited to the mucosa.
In UC, the drugs such as 5-aminosalicylic acid, budesonide, and beclomethasone are used. In patients who have required, at least, two courses of corticosteroid therapy in the preceding 12 months, the British Society of Gastroenterology recommends the escalation of the treatment by using a thiopurine, antitumour necrosis factor (TNF) therapy, vedolizumab, or tofacitinib [5].
2. Biological Treatment of IBD
In the case reports described in the later part of this article, adalimumab, infliximab, and vedolizumab were used. The first two agents belong to the group of TNFα inhibitors with the structure of IgG1. TNFα is a cytokine that plays an essential role in the pathogenesis of several inflammatory disorders; it is secreted by macrophages and T cells and has strong proinflammatory effects. It also plays a relevant role in the immune responses against microorganisms and neoplastic cells. Its main action, among others, is activation of pathways leading to apoptosis and cell necrosis [7]. Increased TNFα concentrations are seen in several autoimmune diseases [8].
Infliximab—a chimeric human-mouse antibody with high affinity for human TNFα—was first launched in 1998 and was the first biological agent approved for the treatment of moderate-to-severe CD and UC. Studies have demonstrated efficacy of infliximab for the induction of remission and maintenance in patients, including those with complicated disease (such as fistulising disease) [9, 10]. Apart from IBD, infliximab is also indicated for ankylosing spondylitis, psoriasis, and psoriatic arthritis [10]. The results of long-term prospective studies by Lichtenstein et al. [11] showed that therapy with infliximab involves a similar risk of death as in case of classical medicinal products; however, infliximab was associated with a more frequent occurrence of serious infections and autoimmune and demyelinating diseases.
Adalimumab—a recombinant human antibody against TNFα—is indicated for use in moderate-to-severe active rheumatoid arthritis when previously administrated therapy with immunosuppressants, glucocorticosteroids, or infliximab was poorly tolerated or inefficient. Additionally, adalimumab induces apoptosis in human monocytes [12]. Early commencement of a biotherapy slows down the progression of the disease [13] and allows the avoidance of polytherapy [14].
Therapy with adalimumab is considered to be relatively safe [15]. The results of the study by Tanaka et al. [16] demonstrated that four years after starting adalimumab treatment, therapy was continued in 62% of patients. However, Lehtola et al. [17] in a 2-year observation of 100 patients with nonspecific IBD noted that just 29 remained in remission. Sixty-three patients discontinued the therapy, and 36 patients with CD underwent a surgery procedure to manage symptoms of the underlying condition [17]. Adalimumab is highly effective in treating fistulising CD, and its effectiveness in closing gaps has been shown in both adults and children [18–20]. The agent can be also used in maintenance treatment to sustain remission. Before initiating treatment with adalimumab, the presence of TB and opportunistic infections (especially P. jiroveci, but also Hepatitis B and C viruses should be taken into account) must be excluded [21]. The authors of another study indicated efficacy of adalimumab in patients with small intestine strictures [22]. In the multicentre study, CREOLI Buhnik et al. demonstrated that 64% of patients with symptomatic small bowel stricture (SSBS) did not have to undergo additional therapeutic interventions while using adalimumab [22]. Due to increased risk of lung and head/neck cancers, caution should be exercised in smokers and patients with COPD [5].
Vedolizumab (marketed in the EU and USA since 2014) is a new agent indicated for use in IBD. Vedolizumab is a novel therapeutic monoclonal antibody acting selectively in the gut via binding to the α4β7 integrin present on activated B and T cells. This protein is a receptor binding the mucosal addressin cell adhesion molecule 1 (MAdCAM1), and its blocking inhibits migration of lymphocytes into the gut, thus reducing local inflammations [23, 24]. This mode of action does not result in systemic immunosuppression and, consequently, should not increase the risk of cancer or opportunistic infections, including TB. Those findings were confirmed by Ng et al. [25] where TB among study participants was observed rarely and reactivation of HBV and HCV infections was not seen [26]. Results of the subsequent study by Colombel et al. [27] involving 2,830 patients with nonspecific IBD demonstrated occurrence of TB, sepsis, and Clostridium infections in up to 0.6% patients. Results from numerous studies indicate that vedolizumab is efficient in inducing and sustaining remission and is considered to be safe and well tolerated [23, 24, 26, 28]. Studies involving patients with UC suggest that vedolizumab is effective, especially as a second-line treatment after previous therapy with TNFα inhibitors [28, 29]. The results of the study of Reenaers et al. [30] demonstrate its superior efficacy as a first-line biological treatment in patients with moderate-to-severe IBD. Despite this, it is still recommended to not use vedolizumab in patients with active TB and to detect and treat latent TB in each patient before initiating vedolizumab [31].
3. Biological Treatment and Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex which includes M. tuberculosis, M. bovis, and M. africanum. In the initial stage, M. tuberculosis cells are phagocytized by macrophages. They rapidly multiply inside the dead macrophages, and after disintegration of macrophages, mycobacteria form granulation tissue composed of granular caseation necrosis and attack the successive cells. At this point, activation of T cells and intensification of cellular responses are observed. Initially, the infection may be asymptomatic; however, TB bacteria can remain latent for many years and then, in favourable conditions, become active. Therefore, latent (LTBI), as well as an active tuberculosis, infection should be excluded in patients who qualify for immunosuppressive treatments, especially those with anti-TNFα agents [32].
Due to the airborne route of infection, the lung is the predominant site of TB. The clinical presentation is nonspecific. Typically, a chronic cough and, less often, haemoptysis or dyspnoea are observed. On physical examination, especially in the initial stages of the disease, auscultatory changes may be absent. General symptoms of TB include low-grade fever, hyperhidrosis, decreased appetite, and weight loss. However, it should be noted that the tuberculous process can affect any organ of the body, especially when it comes to hematogenous spread [33].
TB is an uncommon complication of treatment with TNFα inhibitors; however, studies in patients with rheumatic diseases revealed increased risk for TB in patients with biotherapies. In these studies, 0.21% of patients treated with infliximab, 0.2% treated with adalimumab, and 0.05% treated with etanercept developed tuberculosis during the course of therapy [33].
Tests for the diagnosis of pulmonary tuberculosis disease include a chest X-ray examination and the gamma interferon (IFN-γ) release assay (IGRA), which provides an alternative to a routine tuberculin test (of a lower diagnostic value, especially in patients previously vaccinated with BCG) [34]. It should be noted that false-negative IGRA test results may occur in patients with impaired cell-mediated immune responses. Detecting the presence of the bacteria, especially in a bacterial culture testing, is the conclusive method of TB diagnosis. However it is possible to diagnose TB without positive bacteria culture test results [35]. The sequencing of the entire Mycobacterium genome also appears to be a promising method of TB detection [36].
A typical TB treatment regimen includes two months of rifampicin, isoniazid, ethambutol, and pyrazinamide and then a further four months of rifampicin and isoniazid only. Tuberculosis treatment should be prolonged to, at least, nine months in patients with underlying immunodeficiency or those receiving an immunosuppressive therapy. In the setting of TB induced by a TNF-α inhibitor, this agent should be discontinued, although this may not always be necessary [36]. There is no consensus on whether it is safe to readminister biological treatment in patients with IBD who have a disease exacerbation after withdrawal of a biologic therapy due to active tuberculosis. Similarly, there are no guidelines defining the optimal time for the reintroduction of biological treatment in patients who have started antituberculosis treatment.
The data in the literature are sparse and refer mainly to patients with rheumatic diseases. In one paper describing the readministration of TNFα inhibitors in patients with RA or AS who developed active tuberculosis whilst on anti-TNFα therapy, the median duration from cessation of anti-TNFα therapy to reintroduction was 3 (range 2–7) months in RA and 12 (range 6–29) months in AS [37].
In another study involving 21 patients (two of whom had CD) who developed TB during TNFα blocker treatment, six patients recommenced TNFα blockers at 2 (n = 1), 3 (n = 1), 7.5 (n = 1), and 12 months (n = 3) after the initiation of anti-TB treatment [38].
In another paper describing 13 patients with rheumatic disease who developed active TB infection during treatment with a TNFα inhibitor, the TNFα inhibitor treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment [39].
There are opinions that the biological treatment may be reinitiated after one month of adequate anti-TB therapy (where the susceptibility of the tubercle bacilli to anti-TB agents is shown) [35], but we believe that the biological treatment should be interrupted for, at least, three months if possible.
Preventative TB treatment in patients qualified to receive TNFα inhibitors is recommended in case of positive tuberculin skin or IRGA test results (current or historical), history of ineffectively treated TB, or contact with an individual with active TB disease [35]. The treatment includes isoniazid monotherapy or in combination with rifampicin or rifapentine, or possibly rifampicin in monotherapy. Use of isoniazid in combination with rifapentine allows shortening therapy to three months, with an efficiency of 60–90% [40]. However, TB development is possible despite standard chemoprophylaxis [41, 42].
Since TB usually develops as reactivation of latent infection in adults, it is crucial that the host immune system is able to control the M. tuberculosis population. Cell-mediated immune response based on CD4+ lymphocytes and cytokines (i.e., IFNγ, TNFα, and IL-12) plays a key role. In the course of TB, infected dendric cells (DCs) migrate to lymph nodes where mediated by IL-12 activate T cells into the Th1 phenotype. Those lymphocytes, after returning to the lungs, secrete IFNγ which stimulates infected macrophages to produce TNFα (however, it is also secreted by neutrophils, DCs, and lymphocytes themselves). TNFα has pleiotropic properties associated with cellular response, i.e, when activating macrophages and CD4+ lymphocytes and inducing production of other proinflammatory cytokines, including IFNγ. It seems that, in the course of TB, TNFα plays a vital role in forming and maintaining granulomas. It is suggested that granulomas may be a form of infection control keeping bacteria in one place. Moreover, TNFα accelerates intracellular elimination of mycobacteria; its blocking inhibits phagosomal maturation [43]. Another role of TNFα is induction of apoptosis of infected cells via activation of the caspase cascade. Use of TNFα inhibitors may also cause immunosuppression as a result of intensification of Treg cell responses, which have anti-inflammatory effects [44].
Tests on mice with blocked TNFα indicated that the animals were very susceptible to M. tuberculosis infection, and latent infections were reactivated. As noted, it happened with unchanged responses associated with IFNγ and IL-12. It is suggested that TNFα plays a special role in the control of latent infection. Studies on humans revealed a five-fold increase in the incidence of TB with suppressed TNFα, whereby 25% of patients had miliary tuberculosis and 33% of patients had single extrapulmonary foci, which suggested reactivation of latent infection [44, 45].
It has been shown that anti-TNF biological treatments are associated with increased risk for TB [46] and risk of contracting the disease is higher for anti-TNFα monoclonal antibodies than with soluble TNFα receptor therapy [47].
In view of delayed clearance of biological agents after cessation, patients receiving biological therapies should be monitored for TB for a period of five months after discontinuation of adalimumab therapy and for six months after the end of infliximab treatment [5, 48].
4. Three Forms of Tuberculosis Developed during the Treatment of IBD with Biological Agents
In our clinical practice, as biological treatments are increasingly used, we have noted several cases of TB that developed during treatment with a biological therapy. Below, we briefly present cases of three patients with IBD in whom TB developed soon after initiating treatment with a biological agent. Each of those cases is different; two of those had a dramatic course. Therefore, the aim of this report is to highlight that various types of TB disease should be considered at the point of planning to use a biological treatment not only in patients with IBD but also in other areas of medicine.
Case 1 .
A 25-year-old patient with CD (Figure 1) treated with adalimumab and azathioprine for several months was admitted to hospital due to fever of 40°C that lasted for ten days. Before hospitalization, the patient had been ineffectively treated with cefuroxime. We noted high inflammatory laboratory parameters, a positive IGRA test result, and negative blood culture results. A sputum sample for a culture testing was not obtained. X-ray examination showed features of inflammation of the right middle lobe (RML) (Figure 2). The patient received empirical treatment with ceftazidime, amoxicillin with clavulonic acid, clarithromycin, and acyclovir. M. tuberculosis infection was subsequently confirmed by molecular testing, culture tests, and bacterioscopic examination of bronchial aspirate. After commencing the antimycobacterial treatment, rapid clinical and laboratory improvements were observed. He was maintained on mesalazine and a probiotic for his CD, without worsening. The patient was discharged from hospital and transferred to a tuberculosis sanatorium for further treatment.
Case 2 .
A 37-year-old patient with CD was initially diagnosed as pseudomembranous colitis complicated by perianal fistulae and abscess formations. Right hemicolectomy with partial sigmoid colon resection had been performed in the past. The patient was treated with infliximab for one year. Admission to our clinic was based on the symptoms presented by the patient (dysponea and cough) and the CT results, which indicated the presence of miliary tuberculosis of the lungs (Figures 3 and 4) with mediastinal lymph nodes (Figure 5), hepatic, and splenic involvement. Due to the presence of neurological and mental disorders (agitation and positive psychotic symptoms), a CT of the brain was performed and a sample of cerebrospinal fluid was collected: M. tuberculosis was detected with use of a molecular testing (bacteria culture testing- negative; bacterioscopic examination- negative). The sputum culture for M. tuberculosis and IGRA test results were positive.
Due to laboratory features of bone marrow aplasia, M. tuberculosis spread to the bone marrow was suspected. Treatment included filgrastim, packed red blood cells, platelet concentrate, and fresh frozen plasma. Clinical and laboratory improvements were achieved after initiation of antimycobacterial treatment (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). Management of the patient's CD included mesalazine and a probiotic. The patient was transferred to a sanatorium for further treatment.
Case 3 .
This 41-year-old patient with UC was treated with vedolizumab. He was hospitalized due to recurrent pleural effusion and managed initially in the Department of Thoracic Surgery. After videothoraoscopy, left hemiparesis and neurological symptoms (suggesting stroke occurrence or epileptic seizure) were observed. Based on histopathological examination of pleural fluid, tuberculous pleuritis was diagnosed. The MRI of the brain revealed the presence of tuberculoma of the right parietal lobe (Figures 6 and 7) and tuberculous meningitis. Due to deteriorating respiratory failure, the patient was transferred to the Intensive Care Department were TB was confirmed based on the results of bronchial aspirate culture. Results of the IGRA test were indeterminate. The patient was transferred to our clinic where treatment included management of oedema (dexamethasone, mannitol, and furosemide), sedative (benzodiazepine, haloperidol, and quetiapine), and antimycobacterial agents (amikacin, isoniazid, rifampicin, pyrazinamide, and ethambutol). His UC treatment included mesalazine and hydrocortisone. The neurological and mental symptoms continued despite regression of the lesions noted on repeat MRI of the head. The patient was transferred to a sanatorium for further treatment.
5. Is It Possible to Reduce the Risk of Developing Tuberculosis in Patients with Inflammatory Bowel Diseases Treated with Biological Agents?
It is well known that the risk of developing TB consequent to latent infection in patients with IBD undergoing biological treatment is increased: first of all, because of the disease itself and, secondly, because of treatment. Tuberculosis can present in different locations: not only as pulmonary disease but also up to 91% can have, at least, one extrapulmonary location [49]. Carpio et al. [50] reported 34% of disseminated tuberculosis and 26% of extrapulmonary localization in the population of 50 TB cases in patients with IBD-treated anti-TNF. These findings, as well as our reports, should lead to the conclusion that different forms of tuberculosis can occur in patients with IBD.
The interval between the beginning of treatment and symptoms or diagnosis of tuberculosis varied in different studies from a median of 6 [50–52] to 14.5 months [49]. Consequently, it is clear that the period of observation should not cover only the start of treatment with biological agents.
Unfortunately, even negative initial screening does not exclude the risk of TB development in these patients [49]. The methods used in screening for TB (e.g., anamnesis, chest X-ray, tuberculin skin test, and IGRA) can be unreliable [49]. The IGRA test seems to be more sensitive than skin testing, but it should be noted that immunosuppression can also lead to false-negative results [52]. To minimalize the risk of not detecting the development of TB in patients treated with biological agents, we recommend annual screening with the IGRA test and a chest X-ray, along with a detailed assessment for TB symptoms. If suspicious symptoms are noted, a full diagnostic workup for possible TB should be performed.
It is always better to prevent than to treat. Patients with IBD receiving a biological treatment should probably follow the WHO recommendations on TB infection prevention [53] more closely than healthy people. These recommendations contain administrative and environmental controls and respiratory protection manners that can reduce the risk of TB transmission in the population. The role of triage and sick patient separation systems, effective treatment of those who have already developed TB, and rigorous respiratory hygiene (e.g., cough etiquette) are emphasized. Another way of lowering the risk of TB transmission mentioned in WHO recommendations is cleaning the air by using high-efficiency particulate air (HEPA) filtration or germicidal ultraviolet systems, especially in populations with high TB occurrence [53]. As practicing clinicians, we should inform and encourage all patients to adhere to these recommendations.
6. Conclusions
Preparing patients with CD to receive biological treatments requires accurate identification of latent tuberculosis infections, although this may be difficult due to the effect of the disease itself on the results of diagnostic testing, e.g., IGRA test. Additionally, we should always check for symptoms of the disease, especially as it may be characterized by an atypical course and affect each body organ and system. Negligence in this regard may not only have negative impacts on patients but also have population consequences associated with spreading the infection.
Conflicts of Interest
The authors declare no conflicts of interest.
Figure 1 Coronal t1-weighted MRI image with the gadolinium contrast agent, presenting wall thickening and enhancement of the caecum and proximal ascending colon.
Figure 2 Diffuse consolidation in the lower lobe of the right lung (segment 6) consistent with pneumonia.
Figure 3 Axial chest computed tomography with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 4 Coronal plane chest CT with the presence of innumerable small (2–4 mm) pulmonary nodules with a centrilobular predilection, consistent with miliary tuberculosis.
Figure 5 Axial contrast-enhanced CT scan with the presence of enlarged, necrotic mediastinal lymph nodes at the level of carina.
Figure 6 Axial CT image of the brain with a hypodense lesion in the right parietal lobe, surrounded with oedema.
Figure 7 MRI flair image at the same level depicts oedema surrounding a small, nodal lesion. | Recovering | ReactionOutcome | CC BY | 33489084 | 18,863,547 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
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There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
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Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
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To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
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The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
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Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
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Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
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Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
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In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
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Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
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5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
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FLTAX 32%
Arai et al retro 5‐FU 43%
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5‐FU + platinum 64%
Shitara et al retro Any 40%
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Yukami et al retro FOLFOX 72%
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Osumi et al retro mFOLFOX6 85%
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Iwasa et al retro Any 33%
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Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
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although patients with complete or partial response had long‐term response.
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Unfortunately, few patients responded, and hyperprogressive disease was common.
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Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
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According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
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In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
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,
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In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
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In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | FLUOROURACIL, LEUCOVORIN, METHOTREXATE, NIVOLUMAB, OXALIPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY | 33489132 | 18,997,192 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | FLUOROURACIL, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY | 33489132 | 18,967,261 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic function abnormal'. | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | FLUOROURACIL, LEUCOVORIN, METHOTREXATE, NIVOLUMAB, OXALIPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY | 33489132 | 18,997,192 | 2021-01 |
What was the administration route of drug 'LEUCOVORIN CALCIUM'? | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33489132 | 18,967,261 | 2021-01 |
What was the administration route of drug 'LEUCOVORIN'? | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33489132 | 18,997,192 | 2021-01 |
What was the administration route of drug 'NIVOLUMAB'? | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Oral | DrugAdministrationRoute | CC BY | 33489132 | 18,997,192 | 2021-01 |
What was the administration route of drug 'OXALIPLATIN'? | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33489132 | 18,997,192 | 2021-01 |
What was the dosage of drug 'LEUCOVORIN CALCIUM'? | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | 200 MILLIGRAM/SQ. METER, 1DOSE/2 WEEKS | DrugDosageText | CC BY | 33489132 | 18,967,261 | 2021-01 |
What was the dosage of drug 'NIVOLUMAB'? | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | 240MG/BODY (MONOTHERAPY) | DrugDosageText | CC BY | 33489132 | 18,997,192 | 2021-01 |
What was the dosage of drug 'OXALIPLATIN'? | Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.
Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.
1 INTRODUCTION
We report herein the case of marked improvement of oral intake via third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake and European Cooperative Oncology Group performance status 2. We should consider immune checkpoint inhibitors for microsatellite instability‐high gastric cancer, regardless of the patient's general condition.
Gastric cancer has one of the worst prognoses among all cancer types. Gastrointestinal obstruction due to primary obstruction or peritoneal metastasis is a common complication of advanced gastric cancer. Patients with gastrointestinal obstruction often experience insufficient oral intake, and these patients tend to have worse prognosis. In the JCOG0106 study,
1
sufficient or insufficient oral intake was defined based on whether drip infusion for nutrition support was performed, and the improvement of oral intake was defined as drip infusion not being indicated for > 7 days in patients who previously had insufficient oral intake. Some studies have shown improvement of oral intake with systemic chemotherapy, but these studies were in patients receiving first‐ or second‐line treatment.
1
,
2
,
3
,
4
,
5
,
6
,
7
There have been no published cases of improvement of oral intake with third‐ or later‐line chemotherapy.
Immune checkpoint inhibitors (ICIs) have become widely used for the treatment of various cancers. Nivolumab monotherapy for heavily pretreated gastric cancer was approved as a third‐ or later‐line treatment in Japan in September 2017. However, according to the ATTRACTION‐2 study, the response was very limited.
8
Further, although there are some reports of good response to ICIs in gastric cancer patients, there is no report on the improvement of oral intake by nivolumab monotherapy.
9
To our best knowledge, the current case is the first report of marked improvement of oral intake by third‐line nivolumab monotherapy in a gastric cancer patient with insufficient oral intake.
2 CASE HISTORY
A 76‐year‐old woman presented to our hospital with a stomachache and loss of appetite for 3 months. She was admitted with insufficient oral intake for careful examination and treatment. She had rheumatoid arthritis treated with methotrexate.
2.1 Differential diagnosis, investigations, and treatment
Physical examination revealed no significant findings. The laboratory data on admission are summarized in Table 1. Computed tomography (CT) revealed gastric wall thickening, invasion of the abdominal wall, and regional lymphadenopathy (Figure 1A). Gastrointestinal endoscopy (GIE) revealed Bormann type 3 gastric cancer (Figure 2A). Biopsy of the gastric mucosa showed poorly differentiated adenocarcinoma (Figure 3A, 3B). Immunohistochemical analysis (HercepTest, Dako, Glostrup, Denmark) showed no expression of human epidermal growth factor receptor 2 (score = 0), and HER2/neu amplification was confirmed negative using dual color in situ hybridization (INFORM HER2 Dual ISH DNA Probe Cocktail Assay).
10
The Epstein‐Barr encoding region in situ hybridization was also negative (Figure 3C).
11
Programmed death‐ligand 1 (PD‐L1) protein expression on adenocarcinoma cells was assessed using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies; Carpinteria, CA, USA), and the combined positive score (CPS) was 10 (Figure 3D).
12
Microsatellite instability was high (MSI‐IVD Kit, FALCOⓇ). Therefore, she was diagnosed with unresectable advanced microsatellite instability‐high (MSI‐H) gastric cancer.
12
Table 1 Laboratory data on admission
Hematology
Normal range
White blood cells 8570/μL 3300‐8600/μL
Neutrophils 82.3%
Eosinophils 0.5%
Basophils 0.2%
Monophils 5.3%
Lymphocytes 11.7%
Red blood cells 321 × 104/μL 386‐492 × 104/μL
Hemoglobin 8.7 g/dL 11.6‐14.8 g/dL
Platelets 30.2 × 104/μL 15.8‐34.8 × 104/μL
Coagulation
Normal range
PT 91.6% 80.0%‐120.0%
APTT 28.8 sec 25.0‐38.0 sec
Fibrinogen 517.6 mg/dL 200.0‐400.0 mg/dL
Biochemistry
Normal range
Total protein 5.1 g/dL 6.7‐8.3 g/dL
Albumin 2.3 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.3 mg/dL 0.3‐1.2 mg/dL
AST 15 U/L 13‐33 U/L
ALT 6 U/L 6‐27 U/L
LDH 217 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.46 mg/dL 0.40‐0.70 mg/dL
Na 139 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 8.0 mg/dL 8.7‐10.3 mg/dL
CRP 3.71 mg/dL <0.30 mg/dL
Tumor markers
Normal range
CEA 2.3 ng/mL <5.0 ng/mL
CA19‐9 42.2 U/mL <37.0 U/mL
CA125 61.0 U/mL <26.9 U/mL
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA125, cancer antigen 125; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; CRP, C‐reactive protein; K, potassium; LDH, lactate dehydrogenase; Na, sodium; PT, prothrombin time.
John Wiley & Sons, LtdFigure 1 Computed tomography results. (A) At diagnosis: gastric wall thickening (red circle), invasion of the abdominal wall, and regional lymphadenopathy (red arrow). (B) Before nivolumab monotherapy: gastric wall thickening (red circle), invasion of the abdominal wall, regional lymphadenopathy, and pleural effusion (blue arrow). (C) Two years after nivolumab monotherapy: complete response
Figure 2 Upper gastrointestinal endoscopy results. (A) At diagnosis: Bormann type 3 gastric cancer was observed. (B) Before nivolumab monotherapy: disease progression. (C) Six months after nivolumab monotherapy: tumor shrinkage. (D) Two years after nivolumab monotherapy: complete response (endoscopic biopsy revealed no residual tumor cells)
Figure 3 Histology and immunohistochemistry of the gastric mucosal biopsy specimen. (A) Hematoxylin‐eosin stain (low‐power field) indicating poorly differentiated adenocarcinoma. (B) Hematoxylin‐eosin stain (high‐power field) indicating poorly differentiated adenocarcinoma. (C) Epstein‐Barr virus‐encoded RNA in situ hybridization was negative. (D) Programmed death‐ligand 1 staining; the combined positive score ≥ 10
She underwent gastrojejunal bypass surgery in July 2017, but her oral intake did not sufficiently improve. Therefore, total parenteral nutrition (TPN) was started. A month after the bypass, mFOLFOX6 therapy (oxaliplatin 85 mg/m2 intravenous [IV], l‐leucovorin 200 mg/m2 IV, and 5‐fluorouracil 400 mg/m2 IV bolus followed by 2400 mg/m2 over 46 hours starting on Day 1, every 2 weeks) was started as first‐line treatment. However, CT revealed disease progression after six cycles. Paclitaxel therapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 every month) as second‐line treatment was also ineffective at the first evaluation after 3 cycles. Her general condition did not improve, and she needed TPN after progression on paclitaxel therapy. Although her Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 2, nivolumab monotherapy (3 mg/m2 every 2 weeks until October 2018 and 240 mg/body every 2 weeks from November 2018) was administered as third‐line treatment. Laboratory tests, CT, and GIE before the first administration of nivolumab are summarized in Table 2, Figure 1B, and Figure 2B.
Table 2 Laboratory data at the first administration of nivolumab
Hematology
Normal range
White blood cells 17020/μL 3300‐8600/μL
Neutrophils 92.0%
Monophils 3.5%
Lymphocytes 4.5%
Red blood cells 253 × 104/μL 386‐492 × 104/μL
Hemoglobin 7.0 g/dL 11.6‐14.8 g/dL
Platelets 31.7 × 104/μL 15.8‐34.8 × 104/μL
Tumor markers
Normal range
CEA 6.9 ng/mL <5.0 ng/mL
CA19‐9 52.0 U/mL <37.0 U/mL
Biochemistry
Normal range
Total protein 4.0 g/dL 6.7‐8.3 g/dL
Albumin 1.4 g/dL 4.0‐5.0 g/dL
Total bilirubin 0.2 mg/dL 0.3‐1.2 mg/dL
AST 31 U/L 13‐33 U/L
ALT 24 U/L 6‐27 U/L
LDH 192 U/L 119‐229 U/L
BUN 13 mg/dL 8‐22 mg/dL
Creatinine 0.41 mg/dL 0.40‐0.70 mg/dL
Na 135 mmol/L 138‐146 mmol/L
K 4.0 mmol/L 3.6‐4.9 mmol/L
Ca 7.4 mg/dL 8.7‐10.3 mg/dL
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CA19‐9, carbohydrate antigen 19‐9; CEA, carcinoembryonic antigen; K, potassium; LDH, lactate dehydrogenase; Na, sodium.
John Wiley & Sons, Ltd2.2 Outcome and follow‐up
After four cycles of nivolumab, CT showed that the tumor had shrunk significantly. Her ECOG PS improved from 2 to 0. After 6 months, her oral intake problem had completely improved, and TPN was no longer needed. Upper gastrointestinal endoscopy indicated tumor shrinkage (Figure 2C). CT and upper gastrointestinal endoscopy revealed no residual tumor 2 years after the surgery (Figures 1C and 2D). These findings support that nivolumab monotherapy caused a complete response. She is currently receiving nivolumab monotherapy and has sufficient oral intake (Figure 4).
Figure 4 Changes in CA19‐9 level during the patient's course of treatment. CA19‐9, carbohydrate antigen 19‐9; TPN, total parenteral nutrition; PTX, paclitaxel
Facial paralysis occurred 7 months after nivolumab administration, and we diagnosed it as Bell's paralysis not related to nivolumab. She developed grade 1 liver dysfunction and grade 1 diarrhea as immune‐related adverse events (irAEs).
3 DISCUSSION
We report herein a case of marked improvement of oral intake by third‐line nivolumab monotherapy in a patient with MSI‐H gastric cancer with insufficient oral intake. The first‐ and second‐line treatments were not effective, but she achieved a complete improvement of oral intake with nivolumab and had a complete tumor response after nivolumab monotherapy. To our best knowledge, this is the first case report on improved oral intake from third‐line nivolumab therapy.
Insufficient oral intake is one of the most common complications of gastric cancer. The main causes of insufficient oral intake are gastric outlet obstruction and peritoneal metastasis. Insufficient oral intake is a poor prognostic factor, and Shitara et al reported that the median overall survival (OS) was significantly shorter in patients with insufficient oral intake than in those with sufficient oral intake (5.0 months vs. 12.7 months, P < .05).
3
In previous studies, the rate of improvement of oral intake with first‐line treatment was 32%‐85% (Table 3).
1
,
2
,
3
,
4
,
5
,
6
,
7
Platinum‐containing regimens seem to be more effective than platinum‐free regimens for the improvement of oral intake (Table 3). However, there are no reports of improvement of oral intake in patients receiving third‐ or later‐line treatment. In this case, oral intake was not improved by first‐ and second‐line treatment; additionally, the patient experienced disease progression. However, oral intake was completely improved with third‐line nivolumab monotherapy, and complete tumor response was achieved as observed on imaging studies.
Table 3 Improvement rate of oral intake with first‐line systemic chemotherapy
Trials Phase Regimen Improvement rate Reference
JCOG0106 III 5‐FU ci 41%
1
5‐FU + MTX 57%
JCOG1108/ WJOG7312G II/III 5‐FU + LV 37%
2
FLTAX 32%
Arai et al retro 5‐FU 43%
3
5‐FU + platinum 64%
Shitara et al retro Any 40%
4
Yukami et al retro FOLFOX 72%
5
Osumi et al retro mFOLFOX6 85%
6
Iwasa et al retro Any 33%
7
Note
5‐FU ci, 800 mg/m2/day on days 1‐5, every 4 weeks; MTX + 5‐FU, methotrexate 100 mg/m2 and 5‐FU 600 mg/m2, every week; Best available 5‐FU, 5‐FU ci, or MTX + 5‐FU; PTX, 80 mg/m2/day on days 1, 8, and 15, every 4 weeks; SP, S‐1 80 mg/m2/day on days 1‐21 and cisplatin 60 mg/m2 on day 8, every 5 weeks; S‐1 + PTX iv + PTX ip, S‐1 80 mg/m2/day on days 1‐14, intravenous PTX 50 mg/m2 on days 1 and 8, and intraperitoneal PTX 20 mg/m2 on days 1 and 8; Bolus 5‐FU, 600 mg/m2 on day 1, every week.
Abbreviations: 5‐FU, 5‐fluorouracil; ci, continuous infusion; ip, intraperitoneal administration; iv, intravenous administration; MTX, methotrexate; OS, overall survival; PTX, paclitaxel; retro, retrospective study.
John Wiley & Sons, LtdNivolumab monotherapy is administered for heavily treated gastric cancer according to the ATTRACTION‐2 study. However, in that study, the response rate was 11%, and only three patients had a complete response,
8
,
13
although patients with complete or partial response had long‐term response.
13
Unfortunately, few patients responded, and hyperprogressive disease was common.
14
Many studies have examined predictive factors of the response to ICIs to select patients who may respond to such treatment. Microsatellite instability is one such predictive factor. Janjigian et al reported that the efficacy of cytotoxic drugs was limited among patients with MSI‐H gastric cancer.
15
According to the KEYNOTE‐158 study, which was a single‐arm phase II trial for MSI‐H solid tumors treated with pembrolizumab, the median OS of all patients was 27.8 months, and the median OS of MSI‐H gastric cancer patients was not reached.
16
In the subanalysis of the KEYNOTE‐061 and −062 studies, which were phase III trials of second‐line and first‐line pembrolizumab, respectively, for gastric cancer patients, the median OS of patients with MSI‐H gastric cancer who received pembrolizumab was longer than that of those receiving chemotherapy.
12
,
17
In the current case, the patient had a durable response to third‐line nivolumab because she had MSI‐H gastric cancer. The first‐ and second‐line treatments were not effective, which is consistent with the previous report. The patient has been disease free for 2 years with nivolumab therapy. Therefore, we believe it is important to evaluate the microsatellite instability status before first‐line treatment, and if the patient has an MSI‐H tumor, the response should be evaluated early during first‐line treatment.
PD‐L1 and Epstein‐Barr virus infection have also been reported to be predictive factors for treatment response to ICIs.
18
In the KEYNOTE‐062 study, 21 (11.5%) of 182 patients with a CPS ≥ 10 had MSI‐H tumors, whereas 33 (6.5%) of 506 patients with a CPS ≥ 1 had MSI‐H tumors.
17
CPS is associated with MSI status, and gastric cancer patients with a CPS ≥ 10 have sustained response to ICIs.
Patients with pre‐existing autoimmune disease develop irAEs more frequently than patients without autoimmune disease.
19
,
20
In this case, our patient had rheumatoid arthritis but did not develop severe irAEs. However, patients should still be closely monitored for irAEs during and after ICI administration.
In conclusion, we report herein the first case of marked improvement of oral intake with third‐line nivolumab monotherapy for a gastric cancer patient with insufficient oral intake. This report highlights that ICIs should be administered for MSI‐H gastric cancer, regardless of the patient's general condition.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
TO: Collected information for the case and drafted the initial version of the manuscript. YN: Drafted the initial version of the manuscript. KM: Critical feedback and editing of manuscript. WH: Researched references. KM: Critically edited and revised the initial draft of the manuscript with regard to important intellectual content, with a focus on the psychiatric aspects. All authors discussed the case and commented on the manuscript at all stages and provided their final approval of the version to be published in Clinical Case Reports.
ACKNOWLEDGMENTS
Published with written consent of the patient. | 85 MILLIGRAM/SQ. METER, 1DOSE/2 WEEKS | DrugDosageText | CC BY | 33489132 | 18,967,261 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product use issue'. | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | COBIMETINIB, IPILIMUMAB, VEMURAFENIB | DrugsGivenReaction | CC BY | 33489133 | 18,663,339 | 2021-01 |
What was the administration route of drug 'AMOXICILLIN\CLAVULANIC ACID'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | Oral | DrugAdministrationRoute | CC BY | 33489133 | 18,705,738 | 2021-01 |
What was the administration route of drug 'COBIMETINIB'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | Oral | DrugAdministrationRoute | CC BY | 33489133 | 18,705,738 | 2021-01 |
What was the administration route of drug 'DABRAFENIB'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | Oral | DrugAdministrationRoute | CC BY | 33489133 | 18,705,738 | 2021-01 |
What was the administration route of drug 'IPILIMUMAB'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33489133 | 18,705,738 | 2021-01 |
What was the administration route of drug 'TRAMETINIB'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | Oral | DrugAdministrationRoute | CC BY | 33489133 | 18,705,738 | 2021-01 |
What was the administration route of drug 'VEMURAFENIB'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | Oral | DrugAdministrationRoute | CC BY | 33489133 | 18,705,738 | 2021-01 |
What was the dosage of drug 'AMOXICILLIN\CLAVULANIC ACID'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | 2.25 + 0.75 G/D | DrugDosageText | CC BY | 33489133 | 18,705,738 | 2021-01 |
What was the outcome of reaction 'Osteonecrosis of jaw'? | New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy.
Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.
1 INTRODUCTION
The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated with MRONJ only two times in literature. A woman underwent endovenous chemotherapy with ipilimumab in 2015 for metastatic melanoma. In 2018, while she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone. Ongoing target therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ‐related chemotherapy are needed. A multidisciplinary evaluation is advised.
First reported cases of nonhealing‐exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).
1
During 2004, Novartis, manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs—labeled this product as at risk for osteonecrosis of the jaws (ONJ).
2
Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was renamed as bisphosphonate‐related ONJ (BRONJ).
3
Since then, other BPs and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), and antiangiogenic medications—sunitinib (tyrosine kinase inhibitor).
4
,
5
,
6
,
7
,
8
,
9
,
10
Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv‐aflibercept, ipilimumab, and tocilizumab.
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
With the advent of these new classes of medications, the condition is now more aptly known as medication‐related osteonecrosis of the jaw (MRONJ).
1
Both pathogenesis and associated risk factors not fully comprehended. This majorly reflects on its therapy as indications for surgery (sequestrectomy/curettage with possible reconstruction) vs antibiotic medical therapy (3 g amoxicillin + 1.5 metronidazole per os per day for at least 2 weeks) are still unclear and so great effort is also put in studying and developing complementary treatments, including application of platelet concentrates, ozone therapy, and laser treatment, in order both to prevent MRONJ and to improve healing after surgical treatment of such lesions.
19
Uncertainty increases both for diagnosis and treatment especially for non‐BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.
Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cells, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three‐arm phase III study which compared ipilimumab with a vaccine therapy (gp100) and with their combination,
20
showing improved overall survival in patients undergoing Ipilimumab. Ipilimumab is associated with the risk of immune‐related side effects; sixty percent of immune‐related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune‐related event, and diarrhea, the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high‐dose corticosteroids.
In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.
12
,
17
MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion of it.
In this case report, we describe MRONJ occurred 3 years after the conclusion of treatment with ipilimumab.
2 CASE PRESENTATION
In November 2018, a 58 year‐old‐woman with BRAF‐mutated metastatic melanoma, treated at the immunotherapy unit of our institute, was referred to our oral pathology outpatient clinic. During a regular follow‐up visit, the patient reported that she was experiencing severe pain in the oral cavity for 4 months due to a nonhealing alveolus, after the extraction of the lower right third molar. During this time, the patient had been treated by her dentist for an alveolar osteitis (AO, dry sockets) with 1‐week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash daily socket irrigation. She referred that she had repeated this therapy three times during those months, continuing chlorhexidine 0.2% mouthwash daily socket irrigation among the antibiotic cycles. She referred that, occasionally, she also underwent application of zinc oxide eugenol in her alveolus. Furthermore, the patient had used chlorhexidine 0.2% mouth rinse since day before the extraction. Every treatment tried up until now had been unsuccessful. She had no extra‐oral sign of swelling nor of ongoing abscess. Intraorally, clinical inspection confirmed the presence of a nonhealed alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated bone, surrounded by swollen mucosa (Figure 1).
FIGURE 1 Intraoral inspection revealed the nonhealing alveolus
She exhibited a 3‐day‐old orthopantomography (OPT), which showed radiographic sign of a nonhealed alveolus (Figure 2).
FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction
Her anamnesis was carefully harvested. The patient underwent a surgical resection of a cutaneous melanoma in 2009. Then, in 2015, for lung progression of disease, she was treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles) with complete remission of the disease. During the follow‐up, in 2017 the patient had hepatic progression, and so, due to the presence of the BRAF mutation, she started the treatment with dabrafenib + trametinib (300 + 2 mg per os/die). Due to the G. 3 toxicity (fever) experienced by the patient, the treatment was stopped and was replaced with vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per os/die for 3 weeks then 1‐week pause), still ongoing. She was then taking 1440 mg vemurafenib + 60 mg cobimetinib per os/die at the moment of her tooth extraction. She had no history of smoking nor head and neck radiotherapy. Among all the medications she had undergone, ipilimumab was the only one that has been related to MRONJ.
12
,
17
Staging of the MRONJ was thus performed; it was evaluated to be a “stage 2 MRONJ” according to the AAOMS classification, showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic.”
1
She was thus treated accordingly, starting a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. During the 2‐week follow‐up visit, the patient showed clinical improvement. She referred the ejection of a 10 × 5 mm bone sequestrum after 6 days of therapy and that her symptoms had therefore disappeared. The clinical examination still highlighted an incomplete alveolar healing. Two additional weeks of therapy were prescribed and, after that, the patient obtained a complete healing of the defect (Figure 3). Treatment for the MRONJ was stopped, and the patient was regularly followed up monthly. After 6 months, a new OPT showed complete healing of the alveolus (Figure 4).
FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/die‐ and chlorhexidine 0.2% mouth rinse)
FIGURE 4 Radiographic appearance at OPT after 6 mo of follow‐up, showing complete bone healing
3 DISCUSSION
Several new medications have been added to the potential cause of MRONJ drug list. Among these, ipilimumab has been reported in three published clinical cases as a possible cause of MRONJ, two as single therapy and one in association with denosumab.
12
,
20
As far as literature reports, MRONJ onset was in all cases during ipilimumab therapy or shortly after the conclusion. Our patient suspended the treatment with ipilimumab 3 years before. Dabrafenib, trametinib, vemurafenib, and cobimetinib—the other chemotherapy drugs taken by the patient—have never been reported as possible cause of MRONJ.
Therefore, diagnosis was the first issue we encountered in the management of this case. For the symptoms and the clinical presentation, the differential diagnosis was between alveolar osteitis (dry socket, AO), MRONJ, and osteoradionecrosis (ORN). ORN was the first possibility to be discarded as the patients had no history of head and neck radiotherapy. AO was carefully taken into account prior to start any therapy. The clinical and radiographic appearance was indeed compatible with such disease which is defined as “postoperative pain in and around the extraction site, which increases in severity at any time between one and 3 days after the extraction, associated with a partially or totally disintegrated blood clot within the alveolar socket, with or without halitosis.”
21
Still, as a matter of fact, most recent meta‐analyses show that AO therapy should be more symptomatic
21
,
22
rather than therapeutic, as there is no full comprehension of its pathogenesis and, above all, it is considered as a “self‐limiting” disease. The antibiotic therapy prescribed by the dentist of the patient resulted useless, and no improvement was observed after 4 months even with topic injection of chlorhexidine and zinc oxide eugenol, which are reported between the most successful treatment for AO.
21
,
22
As reported in literature, after the diagnosis, AO, regardless of the therapy, tends to remit in a period of days or weeks, most commonly,
22
while there is no report in scientific literature of AO persisting for several months. AO was thus discarded in the differential diagnosis process.
Furthermore, the presence of a bone sequestrum related to a nonhealing postextraction socket, not visible at the first inspection but ejected during antibiotic therapy, is an event more compatible with MRONJ rather than AO. About the therapy administered, it must be underlined that no guideline exists yet. Consensus conferences
1
advise to begin with antibiotic therapy and then, in case of partial/no response, re‐evaluate the patient for surgery. In our case, antibiotic therapy was administered as first choice and we reached complete healing. Yet, literature
23
warns that partial/no response to antibiotic therapy is a common event, and so is the necessity to complete the therapeutic pathway with surgical approach in order to reach complete healing. Patients must be thus followed up carefully.
As reported before, among the various anticancer therapy agents administered to the patient, ipilimumab was the only drug that could be related to MRONJ. Ipilimumab was approved by the US Food and Drug Administration in March 2011 as an immunotherapy for the management of advanced (unresectable or metastatic) melanoma patients.
12
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen‐4 (CTLA‐4). CTLA‐4 is expressed both in activated T cells and in suppressor T‐regulatory cells, binding to antigen‐presenting cells and therefore diminishing T‐cell responses. The block of the CTLA‐4 is able to improve the antitumor responses of activated T cells. The result is a significant incremented survival in patients with metastatic melanoma undergoing ipilimumab.
18
,
24
The immune response induced by ipilimumab with only 4 cycles of treatment (about 2 months of therapy) can persist for many years, inducing a kind of vaccination against metastatic melanoma. In literature, there are reported cases of ipilimumab‐related ONJ occurred during or shortly after the end of the systemic therapy. The authors suggested that that Ipilimumab may have been involved in the process of bone necrosis by empowering the number of systemic activated T‐cell presence. CTLA4‐deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss.
25
Trauma from regular oral activity or oral surgery (eg, tooth extraction) could increase the demand for this vulnerable bone to mend itself, resulting in localized bone necrosis.
12
Ipilimumab is known to have a 14.7‐day blood half‐life
26
while the patient described in our case had completed Ipilimumab treatment 3 years before. As we have seen, the real advantage of the drug is in the long‐term efficacy with about 20% of patients alive at 5, 7, and 10 years after treatment completion. This long‐term efficacy is due to the immune responses induced by checkpoint inhibitors. Still, just like the anticancer effects, side effects can last for many years.
12
It is conceivable that, similarly to pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies, MRONJ may be also a late side effect under certain circumstances. We suggest that the MRONJ onset may have been co‐caused by the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF‐mutant melanoma can lead to an immune‐stimulating microenvironment by enhancing expression of immune‐stimulating molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines. The cell damage to the tumor by the target therapy may have induced a tumor‐antigen spreading, restimulating T‐cell activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been demonstrated that anti‐BRAF therapy enhances the reactivity and cytotoxicity of T cells.
27
,
28
The re‐activation of such empowered T‐cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to when the patient was on treatment with ipilimumab.
4 CONCLUSIONS
In addition to well‐known medications, MRONJ may be a major adverse reaction to several new‐generation anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended up until now. Even if this paper reports of a single event—in addition to the few other cases reported in literature of ipilimumab MRONJ, the authors recommend caution and strict vigilance in the dental management of patients treated with novel chemotherapy drugs, reported to be at risk for MRONJ. Multidisciplinary evaluation is thus strongly advised; cooperation between the oncologist and the dentist/oral and maxillofacial surgeon may help in taking the best decision in the patient's interest, ensuring the best possible result in the management of relatively recent drugs, which may cause unpredictable side effects. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per os/die) may be arranged in accordance between the surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation may reduce the occurrence of adverse events which, as we have shown in our paper, may result in patient's discomfort and pain. Further studies are needed on a large number of cases, in order to fully understand the relation between ipilimumab and MRONJ, and the possible interference of target therapy.
5 ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Not applicable.
6 CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
AG and AMG: drafted the manuscript. FP: revised the manuscript. FI and PAA: performed scientific supervision.
ACKNOWLEDGMENTS
Not applicable.
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. | Recovered | ReactionOutcome | CC BY | 33489133 | 18,705,738 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coronary artery occlusion'. | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | ASPIRIN, ENOXAPARIN, HEPARIN SODIUM, TICAGRELOR | DrugsGivenReaction | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemodynamic instability'. | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | ASPIRIN, ENOXAPARIN, HEPARIN SODIUM, TICAGRELOR | DrugsGivenReaction | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
What was the administration route of drug 'ASPIRIN'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33489138 | 18,639,018 | 2021-01 |
What was the administration route of drug 'HEPARIN SODIUM'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33489138 | 18,639,018 | 2021-01 |
What was the administration route of drug 'TICAGRELOR'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33489138 | 18,639,018 | 2021-01 |
What was the dosage of drug 'ASPIRIN'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | 300 MG | DrugDosageText | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
What was the dosage of drug 'ENOXAPARIN'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | 300 MG | DrugDosageText | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
What was the dosage of drug 'HEPARIN SODIUM'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | 7500 IU | DrugDosageText | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
What was the dosage of drug 'TICAGRELOR'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | 180 MG | DrugDosageText | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
What was the outcome of reaction 'Coronary artery occlusion'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Fatal | ReactionOutcome | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
What was the outcome of reaction 'Coronary artery thrombosis'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Fatal | ReactionOutcome | CC BY-NC-ND | 33489138 | 18,639,018 | 2021-01 |
What was the outcome of reaction 'Haemodynamic instability'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Fatal | ReactionOutcome | CC BY-NC-ND | 33489138 | 18,635,933 | 2021-01 |
What was the outcome of reaction 'Heparin-induced thrombocytopenia'? | Coronary thrombosis due to heparin-induced thrombocytopenia after percutaneous coronary intervention: Easy to miss, uneasy to prevent.
In case of unexplained post-PCI coronary thrombosis, a HIT should be always considered. A pragmatic approach with bivalirudin may be reasonable, even in absence of confirmed laboratory diagnosis.
1 INTRODUCTION
Heparin‐induced thrombocytopenia (HIT) is a rare immunological reaction to heparin leading to both arterial and venous thrombosis. HIT is infrequent and its clinical features inconstant, so after a percutaneous coronary intervention (PCI) a correct diagnosis may be missed with a negative prognostic impact. We describe an illustrative case.
Heparin‐induced thrombocytopenia (HIT) is a well‐known prothrombotic condition associated with the use of heparin or its derivatives. Treatment consists in the replacement with an alternative anticoagulant, but diagnosis may be challenging because of variable onsets and absence of the typical fall of platelet count. We describe an atypical presentation of HIT with a subsequent missed diagnosis discussing about possible preventive proceedings.
2 CASE REPORT
A 68‐year‐old diabetic, hypertensive male patient was admitted to our cath‐lab for anterior ST elevation acute myocardial infarction (STEMI) at 10 PM Four months before he had been hospitalized for pneumonia and respiratory distress. At admission, vital parameters were stable and blood samples were unremarkable except for a mild thrombocytosis (431 000/mm3) and elevated high‐sensitive troponin. Coronary angiography (CA) revealed the occlusion of left descending artery (LDA) (Figure 1, Panel A). We performed a primary percutaneous coronary intervention (PCI) positioning a drug‐eluting stent (DES) both at proximal LDA and at first diagonal branch with a good angiographic result (Figure, Panel B). During PCI, we administered unfractionated heparin (UFH) 7500 UI), acetyl‐salicylic acid 300 mg intravenously and ticagrelor 180 mg orally. During PCI, the activated clotting time was 255 s. Soon after PCI, we did not observe any complication. Postprocedural biology revealed a significant increase of troponin and a mild hyperglycemia. On day 2, in the morning laboratory tests confirmed the alterations of the day before; platelet count was 339 000/ mm3. At 2 PM of the day 2, 14 hours after PCI, we performed a new urgent CA because of chest pain with inferior ST elevation. A second CA showed an occlusion of proximal right coronary artery (RCA) (Figure, Panel C) and patent LDA. We performed a primary PCI with DES of RCA obtaining ST‐T normalization and remission of chest pain. During PCI, we administered UFH 7500 UI intravenously. An extraction for postprocedural blood count was performed, but 2 hour after the second PCI, the patient experienced a hemodynamic instability. A bedside echocardiogram showed a free wall rupture of left ventricle. Despite cardiopulmonary resuscitation maneuvers, inotropes, and pericardiocentesis, after 30 minutes, we ascertained the exitus. Biology, obtained 2 hours later, revealed a severe decrease in platelet count (88,000/mm3). Because of the rapid exitus, we were not able to perform laboratory tests specific for HIT. Autopsy showed fresh thrombosis of both RCA and LDA. Following the 4 T’s rule, a HIT was highly probable (1). In fact, the patient experienced a fall of platelet count superior than 50%, with a thrombotic event related to the administration of UFH without an alternative cause of thrombocytopenia.
Figure 1 A, Occlusion of LDA at CA; B, Angiographic result after stenting of LDA and first diagonal; C, Occlusion of RCA; D, angiographic result after stenting of RCA. LDA: left descending artery; CA: coronary angiography; RCA: right coronary artery
3 DISCUSSION
HIT is an immune‐mediated decrease of platelet count associated with the use of heparin and its derivatives. The formation of heparin/platelet factor 4 (PF4) complexes and their immunogenicity is the pathological basis of the HIT that typically consists in a fall of the platelet count by more than 30%‐50%. The prevalence varies from 0.1% to 5% in different observational studies.
1
In up to 50% of patients with a diagnosis of HIT, a thrombotic complication is described: this association is defined HIT with thrombosis (HITT).
1
The diagnosis of HIT begins from clinical aspects but should be confirmed by laboratory tests. The 4 T’s Clinical Scoring System is the most used tool for excluding a HIT because of its strong negative predictive value and “ease of use”.The positive predictive value varies from 10% for an intermediate score (4 points) to 80% for a high score (8 points). In case of intermediate or high probability of HIT, immunological or functional assays should be rapidly performed.
1
Thrombocytopenia appears 5‐10 days after heparin exposure in 60% of cases. In 30% of cases, a rapid onset, immediately after exposure, is also described. Rarely, a delayed onset may occur up to 3 weeks after exposure.
2
As UFH is the most used anticoagulant in the cath‐lab, patients undergoing a PCI have a not negligible risk of HIT. In literature cases of coronary thrombosis after PCI with typical HIT but also atypical cases without thrombocytopenia are described.
3
,
4
,
5
The impact of HIT on coronary thrombosis after a PCI has been also described. In a retrospective study evaluating patients undergoing a PCI with an ischemic recurrence within 24 hours, one patient out of four had a diagnosis of HIT. Interestingly, the typical platelet count decrease was not always present.
6
The management of HIT consists in the prompt interruption of heparin administration and the use of alternative anticoagulants as direct thrombin inhibitors (DTI). Bivalirudin, a synthetic analogue of hirudin, is strongly recommended for STEMI patients with HIT.
1
,
7
In our report, the onset of thrombocytopenia is rapid, about 16 hours from the first UFH exposure and we missed the diagnosis of HIT because of the absence of typical fall of platelet count in the period between the first and the second STEMI. So, an early myocardial re‐infarction postprimary PCI had been erroneously attributed to ‘coronary’ causes rather than a prothrombotic condition and a bolus of UFH had been administered during the second PCI. After a careful history, the high risk of HIT probably was related to the administration of enoxaparin during the recent hospitalization for pneumonia.
A recent use of UFH or derivatives should be routinely investigated before a PCI. Moreover, in case of early coronary thrombosis, even within 24 hours, especially if unexplained (eg, coronary thrombosis in nonculprit coronary arteries or not related to stent malapposition/under‐expansion), a HITT should be always suspected. Nevertheless, at the same time the laboratory tests for HIT should be started. As this possibility is rare, a more extensive utilization of bivalirudin is reasonable. About an eventual over‐utilization of bivalirudin, we should consider that it is a therapeutic option in the setting of acute coronary syndromes, independently from the diagnosis of HIT, even if with a lower level of recommendation.
8
Atypical rapid HITT may be arduous to recognize. An approach based on thrombosis and clinical setting rather than on laboratory tests could prevent serious events.
4 CONCLUSION
HIT is an infrequent complication after PCI. As frequently atypical, a correct and prompt diagnosis may be missed. A more extensive use of bivalirudin in unexpected and early coronary thrombosis after PCI could be a reasonable strategy to prevent HITT.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
All authors were involved in the clinical management of this patient and contributed to the preparation of this manuscript.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ACKNOWLEDGMENTS
Published with written consent of the patient. | Fatal | ReactionOutcome | CC BY-NC-ND | 33489138 | 18,639,018 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Torsade de pointes'. | Torsades de pointes after prolonged intravenous amiodarone therapy for atrial fibrillation.
Amiodarone can induce TdP; therefore, it should be avoided as a first choice for therapy in patients without heart disease. Careful QT interval monitoring, especially during intravenous use, can prevent development of this life-threatening arrhythmia.
1 INTRODUCTION
The case of a 71‐year‐old woman with rapid atrial fibrillation (AFib) who underwent electrical cardioversion and intravenous amiodarone therapy. QT interval prolongation was observed with the development of torsades de pointes (TdP) that required recurrent electrical cardioversion and temporary pacemaker implantation.
Amiodarone is a class III antiarrhythmic agent with a low frequency of pro‐arrhythmic effects and an incidence of TdP of <1.0%.
1
,
2
,
3
Intravenous amiodarone is useful for the treatment of AFib and ventricular tachyarrhythmias.
4
We presented the rare case of a woman with rapid AFib who developed TdP on day 3 of intravenous amiodarone therapy.
2 CASE REPORT
A 71‐year‐old woman with a history of diabetes mellitus and hypertension treated with metformin and bisoprolol 2.5 mg was admitted with palpitations and dyspnea which she has been suffering for the two previous days. An examination revealed wheezing on the base of the lungs and rapid AFib on ECG with QT interval of 326 msec, QTc 405 msec (Figure 1). Electrolytes were in the normal ranges. Transesophageal echocardiogram (TEE) excluded left atrial thrombus and showed preserved left ventricular function. Electrical cardioversion to normal sinus rhythm (NSR) was done and an infusion of amiodarone 1 mg/min for 6 hours and then 0.5 mg/min for 18 hours was started after administrating 150 mg bolus. Usually, we administer intravenous amiodarone for 24 hours after sinus rhythm restoration and perform at least one ECG every 24 hours. In this patient soon after cardioversion, the AFib developed again. Therefore, treatment with the maintenance infusion of amiodarone 0.5 mg/min was continued after the first 24‐hour period. On the third day of the therapy, the rhythm on the ECG was AFib 87/min with slightly prolonged QT/QTc intervals (444 msec, QTc 488 msec) (Figure 2). An electrical cardioversion to normal sinus rhythm (NSR) of 60‐70/min was done again after additional 150 mg bolus of amiodarone had been given. In the evening, recurrent episodes of TdP developed and a number of electrical cardioversions were required (Figure 3). The ECG revealed a markedly prolonged QT interval of 511 msec (QTc 531 msec). The amiodarone was discontinued. An insertion of a temporary pacemaker for 2 days was required to suppress this life‐threatening arrhythmia (Figure 4). The QT interval gradually decreased to its baseline value after cessation of the intravenous amiodarone.
FIGURE 1 ECG on admission revealing rapid atrial fibrillation
FIGURE 2 ECG with AFib on the third day of the hospitalization
FIGURE 3 ECG showing episodes of TdP and markedly prolonged QT interval
FIGURE 4 ECG with temporal pacemaker at 75 bpm
3 DISCUSSION
Amiodarone a class III antiarrhythmic agents is useful for the treatment of atrial and ventricular tachyarrhythmias. This drug has pro‐arrhythmic effects and TdP can develop with a higher incidence after intravenous use.
5
,
6
Amiodarone acts by blocking different ion channels involved in the action potential with a dominant effect on potassium channels and therefore can prolong QT interval. The drug also causes bradycardia by suppressing the sinus node and atrioventricular conduction. Intravenous amiodarone significantly slows intraventricular conduction and does not prevent the inducibility of ventricular tachycardia.
7
,
8
In addition to route, dose, and rate administration, other predisposing factors to amiodarone‐induced TdP may be electrolyte disturbances and bradycardia due to concomitant drugs such as beta‐blockers and/or digoxin.
9
The arrhythmia is more common in women.
10
Our patient was a woman who was being treated regularly with a low dose of beta‐blocker and had already taken it on the day when the amiodarone infusion was started. It may be preferable to avoid initiation of IV amiodarone with concomitant beta‐blocker. The patient was admitted with rapid AFib and signs of left heart failure. Her hemodynamic state was stable. She did not have a history of ischemic heart disease and TEE showed a normal left ventricular function.
The medical management of AFib includes rate or rhythm control. In patients with signs of left heart failure, treatment with beta‐blockers or calcium channel blockers can worsen this condition. In this patient, we preferred rhythm control with the goal of reducing AFib‐related symptoms and improving her quality of life over time.
In stable patients, either pharmacological or electrical cardioversion can be attempted, but pharmacological cardioversion is less effective.
According to current guidelines for the management of atrial fibrillation, pretreatment with amiodarone, flecainide, ibutilide, or propafenone should be considered to facilitate the success of electrical cardioversion. The choice of a specific drug is based on the type and severity of associated heart disease. Owing to extracardiac toxicity of amiodarone, other antiarrhythmic drugs should be considered first whenever possible. Amiodarone is mainly indicated in patients with heart failure.
11
As already mentioned, for our patient we decided to do electrical cardioversion and start an antiarrhythmic drug. Soon after electrical cardioversion to NSR and intravenous amiodarone therapy, her heart rhythm again returned to rapid atrial fibrillation. We continued to treat our patient with IV amiodarone. During this time, she was on ECG monitoring, but without regular measurement of QT interval. On the third day, we gave additional bolus of amiodarone 150 mg and after that did cardioversion. That evening amiodarone‐induced TdP developed. Significant QT prolongation was revealed on the ECG.
According to literature, amiodarone‐induced TdP more commonly occurs within 24 hours after initiation of the therapy.
5
In our case, it occurred on day 3 of the maintenance infusion of amiodarone. On that morning the ECG revealed prolongation of QTc 488 msec as in comparison with ECG on admission (QTc 405 msec). Perhaps at that time we should have stopped the infusion of amiodarone, as well as not giving an additional bolus of amiodarone before the second cardioversion. After restoration of NSR, the rate was in the low normal range. It would have been useful to assess QT/QTc intervals during that day. An excessive QTc prolongation above 500 msec caused the development of TdP in the patient.
4 CONCLUSIONS
Intravenous amiodarone therapy requires careful monitoring of the QT interval and timely discontinuation of the treatment in case of excessive prolongation. It can prevent the development of amiodarone‐induced TdP.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
Irina Nordkin MD, MHA, treated the patient and wrote the manuscript. Tatyana Levinas, MD, and Inna Rosenfeld, MD, treated the patient and revised the manuscript. Majdi Halabi, MD, treated the patient and wrote the manuscript.
ETHICAL APPROVAL
Written consent for publication was obtained from the patient and is available upon request.
ACKNOWLEDGMENTS
We are grateful to all medical staff in the cardiology department who participated in the treatment of this patient. This work was not supported by any institution and company.
DATA AVAILABILITY STATEMENT
All data used during the case report are available from the corresponding author on reasonable request. | AMIODARONE HYDROCHLORIDE, BISOPROLOL, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33489188 | 18,642,824 | 2021-01 |
What was the dosage of drug 'BISOPROLOL'? | Torsades de pointes after prolonged intravenous amiodarone therapy for atrial fibrillation.
Amiodarone can induce TdP; therefore, it should be avoided as a first choice for therapy in patients without heart disease. Careful QT interval monitoring, especially during intravenous use, can prevent development of this life-threatening arrhythmia.
1 INTRODUCTION
The case of a 71‐year‐old woman with rapid atrial fibrillation (AFib) who underwent electrical cardioversion and intravenous amiodarone therapy. QT interval prolongation was observed with the development of torsades de pointes (TdP) that required recurrent electrical cardioversion and temporary pacemaker implantation.
Amiodarone is a class III antiarrhythmic agent with a low frequency of pro‐arrhythmic effects and an incidence of TdP of <1.0%.
1
,
2
,
3
Intravenous amiodarone is useful for the treatment of AFib and ventricular tachyarrhythmias.
4
We presented the rare case of a woman with rapid AFib who developed TdP on day 3 of intravenous amiodarone therapy.
2 CASE REPORT
A 71‐year‐old woman with a history of diabetes mellitus and hypertension treated with metformin and bisoprolol 2.5 mg was admitted with palpitations and dyspnea which she has been suffering for the two previous days. An examination revealed wheezing on the base of the lungs and rapid AFib on ECG with QT interval of 326 msec, QTc 405 msec (Figure 1). Electrolytes were in the normal ranges. Transesophageal echocardiogram (TEE) excluded left atrial thrombus and showed preserved left ventricular function. Electrical cardioversion to normal sinus rhythm (NSR) was done and an infusion of amiodarone 1 mg/min for 6 hours and then 0.5 mg/min for 18 hours was started after administrating 150 mg bolus. Usually, we administer intravenous amiodarone for 24 hours after sinus rhythm restoration and perform at least one ECG every 24 hours. In this patient soon after cardioversion, the AFib developed again. Therefore, treatment with the maintenance infusion of amiodarone 0.5 mg/min was continued after the first 24‐hour period. On the third day of the therapy, the rhythm on the ECG was AFib 87/min with slightly prolonged QT/QTc intervals (444 msec, QTc 488 msec) (Figure 2). An electrical cardioversion to normal sinus rhythm (NSR) of 60‐70/min was done again after additional 150 mg bolus of amiodarone had been given. In the evening, recurrent episodes of TdP developed and a number of electrical cardioversions were required (Figure 3). The ECG revealed a markedly prolonged QT interval of 511 msec (QTc 531 msec). The amiodarone was discontinued. An insertion of a temporary pacemaker for 2 days was required to suppress this life‐threatening arrhythmia (Figure 4). The QT interval gradually decreased to its baseline value after cessation of the intravenous amiodarone.
FIGURE 1 ECG on admission revealing rapid atrial fibrillation
FIGURE 2 ECG with AFib on the third day of the hospitalization
FIGURE 3 ECG showing episodes of TdP and markedly prolonged QT interval
FIGURE 4 ECG with temporal pacemaker at 75 bpm
3 DISCUSSION
Amiodarone a class III antiarrhythmic agents is useful for the treatment of atrial and ventricular tachyarrhythmias. This drug has pro‐arrhythmic effects and TdP can develop with a higher incidence after intravenous use.
5
,
6
Amiodarone acts by blocking different ion channels involved in the action potential with a dominant effect on potassium channels and therefore can prolong QT interval. The drug also causes bradycardia by suppressing the sinus node and atrioventricular conduction. Intravenous amiodarone significantly slows intraventricular conduction and does not prevent the inducibility of ventricular tachycardia.
7
,
8
In addition to route, dose, and rate administration, other predisposing factors to amiodarone‐induced TdP may be electrolyte disturbances and bradycardia due to concomitant drugs such as beta‐blockers and/or digoxin.
9
The arrhythmia is more common in women.
10
Our patient was a woman who was being treated regularly with a low dose of beta‐blocker and had already taken it on the day when the amiodarone infusion was started. It may be preferable to avoid initiation of IV amiodarone with concomitant beta‐blocker. The patient was admitted with rapid AFib and signs of left heart failure. Her hemodynamic state was stable. She did not have a history of ischemic heart disease and TEE showed a normal left ventricular function.
The medical management of AFib includes rate or rhythm control. In patients with signs of left heart failure, treatment with beta‐blockers or calcium channel blockers can worsen this condition. In this patient, we preferred rhythm control with the goal of reducing AFib‐related symptoms and improving her quality of life over time.
In stable patients, either pharmacological or electrical cardioversion can be attempted, but pharmacological cardioversion is less effective.
According to current guidelines for the management of atrial fibrillation, pretreatment with amiodarone, flecainide, ibutilide, or propafenone should be considered to facilitate the success of electrical cardioversion. The choice of a specific drug is based on the type and severity of associated heart disease. Owing to extracardiac toxicity of amiodarone, other antiarrhythmic drugs should be considered first whenever possible. Amiodarone is mainly indicated in patients with heart failure.
11
As already mentioned, for our patient we decided to do electrical cardioversion and start an antiarrhythmic drug. Soon after electrical cardioversion to NSR and intravenous amiodarone therapy, her heart rhythm again returned to rapid atrial fibrillation. We continued to treat our patient with IV amiodarone. During this time, she was on ECG monitoring, but without regular measurement of QT interval. On the third day, we gave additional bolus of amiodarone 150 mg and after that did cardioversion. That evening amiodarone‐induced TdP developed. Significant QT prolongation was revealed on the ECG.
According to literature, amiodarone‐induced TdP more commonly occurs within 24 hours after initiation of the therapy.
5
In our case, it occurred on day 3 of the maintenance infusion of amiodarone. On that morning the ECG revealed prolongation of QTc 488 msec as in comparison with ECG on admission (QTc 405 msec). Perhaps at that time we should have stopped the infusion of amiodarone, as well as not giving an additional bolus of amiodarone before the second cardioversion. After restoration of NSR, the rate was in the low normal range. It would have been useful to assess QT/QTc intervals during that day. An excessive QTc prolongation above 500 msec caused the development of TdP in the patient.
4 CONCLUSIONS
Intravenous amiodarone therapy requires careful monitoring of the QT interval and timely discontinuation of the treatment in case of excessive prolongation. It can prevent the development of amiodarone‐induced TdP.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
Irina Nordkin MD, MHA, treated the patient and wrote the manuscript. Tatyana Levinas, MD, and Inna Rosenfeld, MD, treated the patient and revised the manuscript. Majdi Halabi, MD, treated the patient and wrote the manuscript.
ETHICAL APPROVAL
Written consent for publication was obtained from the patient and is available upon request.
ACKNOWLEDGMENTS
We are grateful to all medical staff in the cardiology department who participated in the treatment of this patient. This work was not supported by any institution and company.
DATA AVAILABILITY STATEMENT
All data used during the case report are available from the corresponding author on reasonable request. | 2.5 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33489188 | 18,642,824 | 2021-01 |
What was the outcome of reaction 'Torsade de pointes'? | Torsades de pointes after prolonged intravenous amiodarone therapy for atrial fibrillation.
Amiodarone can induce TdP; therefore, it should be avoided as a first choice for therapy in patients without heart disease. Careful QT interval monitoring, especially during intravenous use, can prevent development of this life-threatening arrhythmia.
1 INTRODUCTION
The case of a 71‐year‐old woman with rapid atrial fibrillation (AFib) who underwent electrical cardioversion and intravenous amiodarone therapy. QT interval prolongation was observed with the development of torsades de pointes (TdP) that required recurrent electrical cardioversion and temporary pacemaker implantation.
Amiodarone is a class III antiarrhythmic agent with a low frequency of pro‐arrhythmic effects and an incidence of TdP of <1.0%.
1
,
2
,
3
Intravenous amiodarone is useful for the treatment of AFib and ventricular tachyarrhythmias.
4
We presented the rare case of a woman with rapid AFib who developed TdP on day 3 of intravenous amiodarone therapy.
2 CASE REPORT
A 71‐year‐old woman with a history of diabetes mellitus and hypertension treated with metformin and bisoprolol 2.5 mg was admitted with palpitations and dyspnea which she has been suffering for the two previous days. An examination revealed wheezing on the base of the lungs and rapid AFib on ECG with QT interval of 326 msec, QTc 405 msec (Figure 1). Electrolytes were in the normal ranges. Transesophageal echocardiogram (TEE) excluded left atrial thrombus and showed preserved left ventricular function. Electrical cardioversion to normal sinus rhythm (NSR) was done and an infusion of amiodarone 1 mg/min for 6 hours and then 0.5 mg/min for 18 hours was started after administrating 150 mg bolus. Usually, we administer intravenous amiodarone for 24 hours after sinus rhythm restoration and perform at least one ECG every 24 hours. In this patient soon after cardioversion, the AFib developed again. Therefore, treatment with the maintenance infusion of amiodarone 0.5 mg/min was continued after the first 24‐hour period. On the third day of the therapy, the rhythm on the ECG was AFib 87/min with slightly prolonged QT/QTc intervals (444 msec, QTc 488 msec) (Figure 2). An electrical cardioversion to normal sinus rhythm (NSR) of 60‐70/min was done again after additional 150 mg bolus of amiodarone had been given. In the evening, recurrent episodes of TdP developed and a number of electrical cardioversions were required (Figure 3). The ECG revealed a markedly prolonged QT interval of 511 msec (QTc 531 msec). The amiodarone was discontinued. An insertion of a temporary pacemaker for 2 days was required to suppress this life‐threatening arrhythmia (Figure 4). The QT interval gradually decreased to its baseline value after cessation of the intravenous amiodarone.
FIGURE 1 ECG on admission revealing rapid atrial fibrillation
FIGURE 2 ECG with AFib on the third day of the hospitalization
FIGURE 3 ECG showing episodes of TdP and markedly prolonged QT interval
FIGURE 4 ECG with temporal pacemaker at 75 bpm
3 DISCUSSION
Amiodarone a class III antiarrhythmic agents is useful for the treatment of atrial and ventricular tachyarrhythmias. This drug has pro‐arrhythmic effects and TdP can develop with a higher incidence after intravenous use.
5
,
6
Amiodarone acts by blocking different ion channels involved in the action potential with a dominant effect on potassium channels and therefore can prolong QT interval. The drug also causes bradycardia by suppressing the sinus node and atrioventricular conduction. Intravenous amiodarone significantly slows intraventricular conduction and does not prevent the inducibility of ventricular tachycardia.
7
,
8
In addition to route, dose, and rate administration, other predisposing factors to amiodarone‐induced TdP may be electrolyte disturbances and bradycardia due to concomitant drugs such as beta‐blockers and/or digoxin.
9
The arrhythmia is more common in women.
10
Our patient was a woman who was being treated regularly with a low dose of beta‐blocker and had already taken it on the day when the amiodarone infusion was started. It may be preferable to avoid initiation of IV amiodarone with concomitant beta‐blocker. The patient was admitted with rapid AFib and signs of left heart failure. Her hemodynamic state was stable. She did not have a history of ischemic heart disease and TEE showed a normal left ventricular function.
The medical management of AFib includes rate or rhythm control. In patients with signs of left heart failure, treatment with beta‐blockers or calcium channel blockers can worsen this condition. In this patient, we preferred rhythm control with the goal of reducing AFib‐related symptoms and improving her quality of life over time.
In stable patients, either pharmacological or electrical cardioversion can be attempted, but pharmacological cardioversion is less effective.
According to current guidelines for the management of atrial fibrillation, pretreatment with amiodarone, flecainide, ibutilide, or propafenone should be considered to facilitate the success of electrical cardioversion. The choice of a specific drug is based on the type and severity of associated heart disease. Owing to extracardiac toxicity of amiodarone, other antiarrhythmic drugs should be considered first whenever possible. Amiodarone is mainly indicated in patients with heart failure.
11
As already mentioned, for our patient we decided to do electrical cardioversion and start an antiarrhythmic drug. Soon after electrical cardioversion to NSR and intravenous amiodarone therapy, her heart rhythm again returned to rapid atrial fibrillation. We continued to treat our patient with IV amiodarone. During this time, she was on ECG monitoring, but without regular measurement of QT interval. On the third day, we gave additional bolus of amiodarone 150 mg and after that did cardioversion. That evening amiodarone‐induced TdP developed. Significant QT prolongation was revealed on the ECG.
According to literature, amiodarone‐induced TdP more commonly occurs within 24 hours after initiation of the therapy.
5
In our case, it occurred on day 3 of the maintenance infusion of amiodarone. On that morning the ECG revealed prolongation of QTc 488 msec as in comparison with ECG on admission (QTc 405 msec). Perhaps at that time we should have stopped the infusion of amiodarone, as well as not giving an additional bolus of amiodarone before the second cardioversion. After restoration of NSR, the rate was in the low normal range. It would have been useful to assess QT/QTc intervals during that day. An excessive QTc prolongation above 500 msec caused the development of TdP in the patient.
4 CONCLUSIONS
Intravenous amiodarone therapy requires careful monitoring of the QT interval and timely discontinuation of the treatment in case of excessive prolongation. It can prevent the development of amiodarone‐induced TdP.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
Irina Nordkin MD, MHA, treated the patient and wrote the manuscript. Tatyana Levinas, MD, and Inna Rosenfeld, MD, treated the patient and revised the manuscript. Majdi Halabi, MD, treated the patient and wrote the manuscript.
ETHICAL APPROVAL
Written consent for publication was obtained from the patient and is available upon request.
ACKNOWLEDGMENTS
We are grateful to all medical staff in the cardiology department who participated in the treatment of this patient. This work was not supported by any institution and company.
DATA AVAILABILITY STATEMENT
All data used during the case report are available from the corresponding author on reasonable request. | Recovered | ReactionOutcome | CC BY-NC-ND | 33489188 | 18,642,824 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sarcoidosis'. | Diffuse lesions secondary to sarcoidosis mimicking widespread metastatic breast cancer: A case report.
This case of sarcoidosis mimicking metastatic breast cancer serves as a reminder of the need to consider differential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases.
1 INTRODUCTION
A 71‐year‐old woman with a history of breast cancer presented with back pain and diffuse PET‐avid lesions consistent with diffuse metastatic disease but was found to represent biopsy‐proven sarcoidosis. This highlights the need for a broad differential even when the clinical scenario and imaging findings are highly suggestive of metastases.
Breast cancer frequently metastasizes to lymphatics, bone, lung, liver, and brain, with bone being the most common hematogenous route and representing more than 70% of distant metastases.
1
Risk factors for bone metastasis include advanced clinical stage, lymph node metastases, negative progesterone receptor status, and tumor subtype.
2
On CT imaging, metastatic bone lesions can appear as either osteolytic or osteoblastic, or they can have a mix of osteolytic and osteoblastic features; they are most commonly located in the vertebrae and pelvis owing to the rich vascularization of these areas.
3
There are, however, several other conditions that can mimic the imaging findings of metastatic cancer and should be ruled out prior to ascribing the changes seen on imaging to metastatic spread.
One such condition is sarcoidosis, an inflammatory condition with highly variable clinical presentation and a hallmark pathological finding of non‐caseating epithelioid granulomatous inflammation. Sarcoid granulomas most often affect the lungs and lymph nodes in >90% of cases, but can be present in almost any tissue in the body.
4
Bone lesions are present in an estimated 3%‐13% of cases, most commonly in the small bones of the hands and feet; vertebral involvement is rare but has been reported.
5
Vertebral lesions have variable appearance on CT, with existing reports describing lytic, mixed lytic with sclerotic features, and sclerotic appearance.
6
,
7
Much like metastases and some infectious granulomas, sarcoid granulomas display increased avidity for fluorodeoxyglucose (FDG) during PET/CT imaging.
8
Herein, we present a case of a 71‐year‐old female with past medical history significant for breast cancer who was thought to have widely metastatic disease based on clinical picture and imagining findings, but was instead found to have an inflammatory cause for her widespread hypermetabolic bone and soft tissue lesions on biopsy.
2 CASE PRESENTATION
A 71‐year‐old Caucasian female presented with a chief complaint of acutely worsened lower back pain. The pain had come on over the previous two months and was localized over the upper lumbar spine. She reported an increase in intensity of the pain when lying flat. The patient had a longstanding history of chronic back pain, and two previous surgeries for adult tethered cord syndrome, but reported this pain to be significantly worse than what she had experienced before.
Notably, her past medical history included a diagnosis 13 months prior of infiltrating ductal adenocarcinoma of the breast, which had been identified on routine screening mammogram. The tumor was determined on core needle biopsy to be ER (90%), PR (95%), and Her2 (3+) positive, with a Ki67 of 13%. She had undergone a left breast lumpectomy and sentinel lymph node biopsy with negative surgical margins. Final pathology from lumpectomy demonstrated the tumor was grade 2 and 1.2 cm in greatest dimension. Focal DCIS was present with high nuclear grade. The sample was without lymphovascular invasion. Pathology showed one of six sentinel nodes was positive for macrometastatic disease with associated extracapsular extension. Final pathological staging after lumpectomy and sentinel lymph node biopsy was pT1N1aMx.
After lumpectomy, the patient had been treated with adjuvant chemotherapy followed by radiation therapy and hormonal therapy. Her chemotherapy regimen consisted of dose dense paclitaxel, cyclophosphamide, and trastuzumab for a total of six cycles, which was complicated by neutropenic fever following the first dose as well as a persistently infected wound of the toe prompting a dose reduction of paclitaxel and cyclophosphamide for the remaining five cycles, with plans to continue trastuzumab therapy for one year. Her radiation treatment was initiated five weeks following completion of her cyclophosphamide and paclitaxel treatment. Radiation treatment was delivered to the whole breast with high tangents using a hypofractionated course to a total dose of 4256 cGy delivered over 16 fractions followed by a 1000 cGy boost to the tumor bed delivered over five fractions. Given the ER‐positive status of her tumor, the patient was also started on anastrozole at the conclusion of her radiation therapy. Ten months after initial diagnosis and three months after the completion of radiation therapy, a diagnostic mammogram showed no evidence of disease in either breast. The patient was continued on trastuzumab and anastrozole.
Her presentation with acutely worsened back pain occurred one week after completion of the one‐year of adjuvant trastuzumab therapy, and approximately 13 months after breast cancer diagnosis. A review of systems was negative for constitutional symptoms. Physical examination at the time of presentation showed tenderness to palpation midline in the upper lumbar spine, with limited range of motion bidirectionally due to pain. Neurological examination, including assessment of strength and gait, was normal. No laboratories were drawn at this time.
An MRI of the spine was ordered, which showed an abnormal signal and enhancement at L2, L4, and S1 in addition to iliac and sacral lesions consistent with metastatic disease (Figure 1). A follow‐up PET scan demonstrated multifocal hypermetabolic lesions in the mediastinum, hila, spleen, liver, abdominal and inguinal lymph nodes, as well as in multiple bones (SUVmax(range): 3‐5.75) suggestive of widespread and distant metastatic involvement (Figure 2). A biopsy of a liver lesion was planned for confirmation of metastatic disease but results from this failed to confirm the diagnosis of metastasis and showed no signs of malignancy, instead unexpectedly showing granulomatous hepatitis with multiple non‐caseating epithelioid granulomas.
Figure 1 Representative sagittal (A) and coronal (B) MRI sections demonstrating lesions at L2/3 and L4
Figure 2 Representative images from PET/CT scan. (A) PET/CT composite. (B) Coronal section on PET/CT. (C) Axial section of L2/3 lesion. (D) Axial section of L4 lesion
Due to these non‐confirmatory findings on biopsy, the case was reviewed by a multidisciplinary tumor board comprising diagnostic radiology, pathology, oncology, and radiation oncology. The consensus from this session was that, despite the nondiagnostic biopsy results, the patient's imaging findings, clinical findings, and history of breast cancer were most consistent with metastatic disease and palliative radiation therapy with repeat biopsy of a separate site was recommended.
Two weeks later, the patient underwent a CT‐guided biopsy of the left iliac and right side of the L4 vertebral body. These biopsies again failed to demonstrate any evidence of malignancy but instead consistently demonstrated a non‐necrotizing granulomatous pattern of disease. Therefore, metastatic disease was no longer considered the likely diagnosis due to the biopsies of multiple sites failing to demonstrate any evidence of metastatic disease.
A comprehensive workup was performed to evaluate for a possible infectious source for the lesions. A quantiferon test as well as urine and serum Ag/Ab tests for histoplasma, blastomycosis, coccidiomycosis, and treponema was completed with all tests coming back negative. PCR testing of the liver was also negative for acid‐fast bacilli and fungi. On further evaluation, it was noted that one year prior to her breast cancer diagnosis, the patient had complained of a persistent cough with evaluation demonstrating imaging evidence of possible sarcoidosis. She did not receive treatment for sarcoidosis at the time, and instead was instructed to return if her cough worsened. As a result of this additional information and her recent biopsy results demonstrating non‐necrotizing granulomas, the patient was referred to a rheumatologist, and her imaging findings were evaluated for their potential to represent widespread sarcoidosis. However, she still refrained from initiating steroid treatment for sarcoidosis as her back pain was thought to be more consistent with worsening osteoarthritis after consultation with a rheumatologist. A repeat MRI of the lumbar spine four months later demonstrated that the PET‐avid bone and soft tissue lesions were stable and comparable in size with what was seen in the previous MRI, providing further reassurance against a metastatic etiology for these lesions.
3 DISCUSSION
This case report should serve as a cautionary tale describing alternative potential causes of imaging findings consistent with malignancy. Multiple groups have previously described additional cases or highlighted other causes of PET‐avid lesions that mimic malignancy on PET/CT scan that were largely observed during initial cancer staging or incidental findings on imaging. In this case, the patient presented with numerous lesions more than a year after her initial breast cancer diagnosis mimicking a more recurrent/metastatic clinical picture. Our patient presented with back pain, a common presenting symptom in patients with bone metastasis, and was then found to have multiple bone lesions on spine MRI and additional soft tissue involvement on subsequent PET imaging. Based on her past medical history, clinical picture, and corroborating imaging findings, this patient was believed to have metastatic disease for several weeks while awaiting biopsy results that revealed a nonmalignant etiology.
Known nonmalignant causes of FDG‐avid lesions include anything that induces inflammation or increased glucose uptake in tissue, which are commonly of infectious or autoimmune origin. Other groups have reported false positive PET scan findings can be caused by infectious diseases (including mycobacterial, fungal, or bacterial), sarcoidosis, trauma, and post‐operative surgical conditions in the absence of malignancy.
9
,
10
,
11
,
12
,
13
,
14
,
15
,
16
,
17
,
18
,
19
,
20
In fact, a concurrent diagnosis of sarcoidosis has been described in a case report when additional lesions were identified during initial cancer staging workup, but the additional lesions were subsequently determined to be nonmalignant.
21
Other alternative nonmalignant etiologies of bone lesions include fibrous dysplasia of bone, osteonecrosis, osteitis fibrosa cystica, and Paget's disease of bone, among others, can present with PET‐avid lesions on imaging and characteristic laboratory findings including hypercalcemia.
10
,
13
,
14
,
15
,
22
Infectious etiologies also need to be ruled out when PET‐avid bone lesions are identified as disseminated tuberculosis and multifocal osteomyelitis have both been reported to be mistaken for metastases on PET scan.
12
,
16
,
18
Multiple cutoff values have been proposed to distinguish between benign and malignant origins for increased FDG‐avidity. One group proposed an SUV cutoff of 3 for bone metastases with sensitivities ranging from 95.2% to 99.6% and specificity ranging from 75% to 100% for various primary malignancies including breast.
23
Another group evaluating rib metastases found the max SUV was higher in malignancy (3.0 ± 1.8) than in benign causes (2.5 ± 1.1), but had significant overlap and recommended a cutoff of 2.4.
24
Finally, in an evaluation for axillary metastasis as part of the initial workup for newly diagnosed breast cancer, a max SUV cutoff of 2.3 had a sensitivity of 60% and a specificity of 100%. However, no single cutoff is reliable in all circumstances and the range for benign vs. malignant causes overlap. For example, in our patient the SUVmax was 5.75 and 4.91 in two of her bone lesions with numerous areas of soft tissue and lymph nodes having an SUVmax above 3.
While more qualitative metrics, the pattern of disease and other specific imaging findings can be used to try to distinguish between possible etiologies. For example, while the radiographic findings in sarcoidosis are highly variable, it tends to favor a symmetric and central distribution. Another radiographic finding that is commonly attributed to metastatic disease is increasing lymph node size. However, increasing size of lymph nodes on imaging can also have a range of non‐metastatic causes including sarcoidosis, fibrosing mediastinitis, or even a second, primary lymphoma.
11
,
17
,
25
In this case, the patient's clinical presentation and history were consistent with metastatic disease, but her back pain and hypermetabolic lesions were ultimately determined to be nonmalignant in nature representing likely musculoskeletal and sarcoid‐related findings, respectively. Thus, the differential diagnoses in a patient with newly identified lesions on PET/CT should be evaluated according to the clinical scenario as well as specific imaging findings (level of SUVmax, CT or MRI findings). However, without confirmation from tissue biopsy there will always be at least a small amount of uncertainty. Therefore, lymph node and other image‐identified lesions should be biopsied whenever possible to confirm suspected metastases. Unfortunately, such a biopsy may not always be feasible due to complex anatomic location, patient history, or other complicating factors, could delay treatment, and therefore may be omitted in the setting of a clear clinical picture, patient history, and/or inability to obtain tissue biopsy.
4 CONCLUSIONS
In this case, the consistency of the patient's clinical and imaging findings with metastatic disease and the much higher likelihood of metastatic disease vs. other causes in this clinical scenario supported the use of empiric therapy. Regardless, the possibility of another etiology causing similar findings on imaging should be considered and ruled out if at all possible prior to treatment. Empiric radiation therapy is commonly used in the setting of previously biopsy‐proven malignant disease for the purpose of pain palliation or for the prevention of impending anatomic damage (ie, spinal cord compression). However, the likelihood of metastatic disease and urgency of the clinical scenario should drive decision‐making in these situations. Ideally, timely imaging in conjunction with pathologic evidence of malignant disease should be obtained prior to any treatment if at all possible. Unfortunately, however, this is not always possible or routinely practiced in the setting of probable metastatic disease inducing significant pain or impending spinal cord compression.
Overall, this case highlights the need to consider a wide differential of potential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases. In addition, prompt biopsy confirmation of metastatic disease provides significant value through confirmation of the diagnosis even when the clinical and imaging data are suggestive thereby ensuring appropriate treatment.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
HV, BN, and RS: reviewed patient records, drafted the case report, and revised the final manuscript. JH, AF, GM, AW, and MB: participated in direct patient care and provided the patient background and presentation. All authors: revised the final manuscript and gave final approval for publication.
ACKNOWLEDGMENT
Published with written consent of the patient. | ANASTROZOLE, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33489200 | 20,577,721 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neoplasm progression'. | Secondary brain metastases of Ewing's sarcoma presenting with collapse after 6 years of complete remission.
Routine brain imaging with MRI and long-term follow-up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long-term outcome for patients.
1 INTRODUCTION
A 23‐year‐old gentleman came to Emergency Department with first episode of sudden collapse. He had a right pelvic Ewing's sarcoma surgically resected 6 years ago. MRI of the head demonstrated a lesion in right temporal lobe, extending into infratemporal fossa. He was referred to oncology for further management with chemotherapy.
Ewing's sarcoma is a childhood tumor which is rarely seen, occurring in 2.93 children per 1 000 000, more common in male and hardly understood by many clinicians. The definite diagnosis is of Ewing's sarcoma is usually made in tertiary hospital via biopsy and microscopic evaluation of tumor cells and molecular analysis. Ewing's sarcoma usually requires treatment from different specialties including pediatric or adult oncologist, orthopedic surgeons, and other specialists depending on tumor site. Management of Ewing's sarcoma varies greatly among different patients but includes chemotherapy, radiotherapy, and surgical resection. Most of the brain metastases from Ewing's sarcoma usually occur in the range of 20‐30 months from the time of diagnosis of primary tumor. This case report describes the rare presentation of a gentleman who develops single secondary brain metastases of Ewing's sarcoma after 6 years of complete remission.
2 CASE HISTORY
A 23‐year‐old Caucasian gentleman was brought into the Emergency Department after an episode of collapse with loss of consciousness for 2 minutes. Up‐rolling of both eyeballs was seen throughout the episode.
He had been having 2 months history of intermittent pain around left temporomandibular area, not relieved by any analgesics. He had previous history of Ewing's sarcoma found in his right pelvis on May 2013. It was surgically removed via hemipelvectomy on January 2014. Postoperatively, he was continued with 16 courses of chemotherapy and 25 sessions of radiotherapy in total. He was then followed up by oncology department every 6 months for 4 year, followed by annually for 2 years. A chest and pelvic X‐ray was done before every appointment. He was discharged from follow‐up on Jan 2020 disease‐free. Apart from that, he had no other medical or surgical condition.
2.1 Examination
On physical examination, patient was alert and well orientated with Glasgow Coma Scale of 15/15. There was a small bruise to right side of temple with no laceration, possibly due to the collapse. No swelling or tenderness upon palpation was felt on the left side of the face. Upon cranial nerve examination, the only positive sign was a horizontal nystagmus seen in both eyes. There was also no abnormality noted in sensory and motor neurological examination of bilateral upper and lower limbs.
2.2 Investigations
Routine blood test including full blood count, urea and electrolyte, and C‐reactive protein was performed. No abnormality or raised inflammatory marker was noted.
Computed tomography scan of the head was requested. A space occupying lesion at the left temporal lobe extending through the skull base to the left masticator space was found. This warranted for a further contrast‐enhanced magnetic resonance imaging (MRI) of the head. An aggressive large mass lesion measuring 7 cm by 4 cm was seen in the left temporal location, eroding through the skull base, resulting in extracranial component in the infratemporal fossa. It had solid and cystic components with surrounding edema. Medially, the lesion was seen to extend up to the pterygoid plates and the posterior superior nasopharynx on the left side, and a resultant block of the Eustachian tube and a left mastoid effusion was seen. Midline shift to the right of 6mm as a result of mass effect was also noted. CT‐guided biopsy of the left superficial temporal fossa lesion was carried out. Presence of a CD99 + small round blue cell tumor and detection of an EWSR1 rearrangement at 22q12 in 84% of cells via FISH testing are consistent with diagnosis of recurrent Ewing's sarcoma.
After that, patient had a CT thorax, abdomen, and pelvis with contrast, showing no evidence of visceral metastases disease. He then proceeded to have a whole‐body SPECT and whole‐body PET FDG, showing single brain metastases with elevated activity in left skull base region and no evidence to suggest extracranial or bone metastases elsewhere Figures 1, 2.
FIGURE 1 Axial MRI images A (T1W), B (T2W), C (T2 PROPELLER), D (FSPGR), and E (Diffusion weighted) demonstrating 7 cm by 4 cm lesion which consists of solid and cystic components with surrounding edema. Mass effect of the lesion causes midline shift of 6 mm to the right
FIGURE 2 Sagittal (A) and coronal (B) MRI images demonstrating lesion in left temporal lobe eroding through base of skull with extracranial extension in the infratemporal fossa. Lesion extends up to pterygoid plates and posterior superior nasopharynx on the left side
2.3 Outcome and follow‐up
The patient was then referred back to the initial oncology department for further management. At time of writing this report, the patient has had five courses of chemotherapy, ifosfamide, and etoposide (Doxifos) and had an MRI showing shrinkage of tumor by more than 50% after second course of chemotherapy. He will be continued with more courses of Doxifos and possible surgical resection Figures 3 and 4.
FIGURE 3 Dramatic regression of both intracranial and extracranial components of tumor is seen after chemotherapy. Comparison of images before chemotherapy (right) and after chemotherapy (left) are seen in A (axial view), B (sagittal view) and C (coronal view)
FIGURE 4 Figure illustrating chronological order of patient's disease and progression
3 DISCUSSION
Ewing's sarcoma is a very rare type of bone or soft tissue tumor, predominantly affecting children, adolescents, and young adult. It is the however the second most common type of malignant bone tumors after osteosarcoma. The annual incidence of Ewing's sarcoma is around 1.8 per million for age 0‐14 and 3.7 per million for age 15‐24. The incidence rate is highest among the 15‐19 age group, which is 4.8 per million per year. It is also more commonly seen in male as compared to female with a ratio of 1.89:1.
1
Ewing's sarcoma is more common among Caucasians as compared to the other races.
2
,
3
,
4
Our patient, a 17‐year‐old Caucasian male at time of discovery, would fit into the category of highest incidence. Due to rarity of disease, the cause of Ewing's sarcoma is still unknown as most of the cases appear sporadically. Studies have shown that the t(11;22)(q24;q12) translocation is found in about 85% of Ewing's sarcoma, which leads to an EWS/FLI1 fusion gene but more studies have to be done to further understand the significance.
5
It is in fact one of the most aggressive cancer with high metastatic potential.
6
On first discovery of right pelvic Ewing's sarcoma 7 years ago, our patient had undergone a hemipelvectomy, coupled with a regimen of neo‐adjuvant chemotherapy, 25 sessions of radiotherapy, and a regimen of adjuvant chemotherapy. In fact, studies on pelvic Ewing's sarcoma have shown that surgery coupled with neo‐adjuvant chemotherapy and radiotherapy would produce better outcome as compared to radiotherapy coupled with neo‐adjuvant chemotherapy or radiotherapy alone.
7
,
8
,
9
,
10
,
11
,
12
,
13
However, the results could be biased due to the fact that smaller sized tumors were managed surgically while large tumors were managed with neo‐adjuvant chemotherapy and radiotherapy. It is also seen that neo‐adjuvant chemotherapy would provide benefit on local control as compared to surgery with radiotherapy alone.
14
Before surgical resection, our patient had neo‐adjuvant chemotherapy. He had undergone of 8 cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) chemotherapy regime. VIDE chemotherapy is widely used across Europe in management of Ewing's sarcoma as it is considered the most effective treatment. It is also associated with low rate of adverse reactions. Our patient had an episode of neutropenia‐related fever during the course of VIDE, which is seen in 65.8% of the patients receiving this chemotherapy regimen.
15
After 8 courses of VIDE, our patient had 25 courses of neo‐adjuvant radiotherapy, followed by surgical resection. He was then further managed with another 8 cycles of adjuvant chemotherapy. This chemotherapy regimen includes vincristine, actinomycin D or also known as dactinomycin, and ifosfamide (VAI). VAI is one of the most commonly used consolidation regimen. In fact, few studies and trial had been carried out to study on replacement of ifosfamide with cyclophosphamide due to the higher modifications needed for VAI; however, both of them were found to have similar efficacy.
16
,
17
There are also ongoing studies on different chemotherapy agents that could be incorporated in consolidation regimen for Ewing's sarcoma including doxorubicin, busulfan, mephalan, or even zoledronic acid.
18
,
19
,
20
After 6 years of complete remission, our patient had an episode of collapse and was found to develop secondary brain metastasis. Brain metastasis is rare among children with solid tumors, usually presenting with seizure or hemiparesis.
21
However, Ewing's sarcoma is the most common tumor causing secondary brain metastasis.
22
,
23
This might be due to the consequence of chemotherapy effectively suppressing systemic metastases while leaving the central nervous vulnerable due to blood‐brain barrier.
24
A study of 335 Ewing's sarcoma patients shows that only 3.3% had brain metastases.
25
Another study of 80 children with Ewing's sarcoma shows higher rate of 8.8% with secondary brain metastases.
21
Due to the fact that Ewing's sarcoma is one of the commonest childhood tumor to develop brain metastases, prophylactic central nervous system irradiation and intrathecal methotrexate as part of initial therapy had been advocated in management of newly diagnosed Ewing's sarcoma in the past to prevent occurrence of central nervous system Ewing's sarcoma. However, the overall risk of secondary brain metastases was the same; hence, current regimens do not include these measures.
26
The overall survival rate of secondary brain metastasis from Ewing's sarcoma is grave, usually with a period of 2 months from time of brain metastasis which improved to 7 months on surgical resection.
22
,
27
,
28
However, two cases of long‐term survival were reported. They had combination of surgical resection, chemotherapy, and radiotherapy.
25
,
29
The literature on secondary brain metastases from Ewing's sarcoma is scarce. Most of them are focused on children with very minimal literature on young adults. This might be due to the fact that patients could be asymptomatic or present with minor symptoms such as headache.
30
Further research or study is definitely required.
This paper puts forward a proposal for routine imaging such as MRI scan of head on follow‐up of patient with Ewing's sarcoma. Firstly, this might provide a more accurate understanding on the incidence of secondary brain metastases in Ewing's sarcoma. Secondly, this could help in diagnosing any brain metastases before the tumor grows large. Thirdly, this could improve the outcome by enabling surgical resection coupled with chemotherapy or radiotherapy when the tumor is small.
This case serves to improve our understanding toward the rare occurrence of secondary brain metastases of Ewing's sarcoma after long period of complete remission, as well as highlighting the importance of further study and research in this field. Routine brain imaging on follow‐up of patient with Ewing's sarcoma could be the next step forward in improving our understanding of this disease as well as improving long‐term outcome of patients.
Learning points
Ewing's sarcoma is the most common childhood tumor to cause secondary brain metastasis.
22
,
23
Surgical resection coupled with chemotherapy and radiotherapy provides the best long‐term outcome in management of primary or secondary Ewing's sarcoma.
Routine brain imaging and long‐term follow‐up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long‐term outcome for patients.
CONFLICT OF INTEREST
The author of this study has no conflict of interest to declare.
AUTHORS’ CONTRIBUTION
JZP: Conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, and critical revision for important intellectual content.
ETHICAL APPROVAL
No approval is required.
Supporting information
App S1
Click here for additional data file.
ACKNOWLEDGMENTS
The author would like to acknowledge the patient for providing consent to share his case. The author would also like to acknowledge the histopathologist and radiologist of Sheffield Teaching Hospital for their contribution. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
Data are available in article supplementary material. | DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, VINCRISTINE | DrugsGivenReaction | CC BY | 33489215 | 18,907,873 | 2021-01 |
What was the dosage of drug 'DOXORUBICIN'? | Secondary brain metastases of Ewing's sarcoma presenting with collapse after 6 years of complete remission.
Routine brain imaging with MRI and long-term follow-up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long-term outcome for patients.
1 INTRODUCTION
A 23‐year‐old gentleman came to Emergency Department with first episode of sudden collapse. He had a right pelvic Ewing's sarcoma surgically resected 6 years ago. MRI of the head demonstrated a lesion in right temporal lobe, extending into infratemporal fossa. He was referred to oncology for further management with chemotherapy.
Ewing's sarcoma is a childhood tumor which is rarely seen, occurring in 2.93 children per 1 000 000, more common in male and hardly understood by many clinicians. The definite diagnosis is of Ewing's sarcoma is usually made in tertiary hospital via biopsy and microscopic evaluation of tumor cells and molecular analysis. Ewing's sarcoma usually requires treatment from different specialties including pediatric or adult oncologist, orthopedic surgeons, and other specialists depending on tumor site. Management of Ewing's sarcoma varies greatly among different patients but includes chemotherapy, radiotherapy, and surgical resection. Most of the brain metastases from Ewing's sarcoma usually occur in the range of 20‐30 months from the time of diagnosis of primary tumor. This case report describes the rare presentation of a gentleman who develops single secondary brain metastases of Ewing's sarcoma after 6 years of complete remission.
2 CASE HISTORY
A 23‐year‐old Caucasian gentleman was brought into the Emergency Department after an episode of collapse with loss of consciousness for 2 minutes. Up‐rolling of both eyeballs was seen throughout the episode.
He had been having 2 months history of intermittent pain around left temporomandibular area, not relieved by any analgesics. He had previous history of Ewing's sarcoma found in his right pelvis on May 2013. It was surgically removed via hemipelvectomy on January 2014. Postoperatively, he was continued with 16 courses of chemotherapy and 25 sessions of radiotherapy in total. He was then followed up by oncology department every 6 months for 4 year, followed by annually for 2 years. A chest and pelvic X‐ray was done before every appointment. He was discharged from follow‐up on Jan 2020 disease‐free. Apart from that, he had no other medical or surgical condition.
2.1 Examination
On physical examination, patient was alert and well orientated with Glasgow Coma Scale of 15/15. There was a small bruise to right side of temple with no laceration, possibly due to the collapse. No swelling or tenderness upon palpation was felt on the left side of the face. Upon cranial nerve examination, the only positive sign was a horizontal nystagmus seen in both eyes. There was also no abnormality noted in sensory and motor neurological examination of bilateral upper and lower limbs.
2.2 Investigations
Routine blood test including full blood count, urea and electrolyte, and C‐reactive protein was performed. No abnormality or raised inflammatory marker was noted.
Computed tomography scan of the head was requested. A space occupying lesion at the left temporal lobe extending through the skull base to the left masticator space was found. This warranted for a further contrast‐enhanced magnetic resonance imaging (MRI) of the head. An aggressive large mass lesion measuring 7 cm by 4 cm was seen in the left temporal location, eroding through the skull base, resulting in extracranial component in the infratemporal fossa. It had solid and cystic components with surrounding edema. Medially, the lesion was seen to extend up to the pterygoid plates and the posterior superior nasopharynx on the left side, and a resultant block of the Eustachian tube and a left mastoid effusion was seen. Midline shift to the right of 6mm as a result of mass effect was also noted. CT‐guided biopsy of the left superficial temporal fossa lesion was carried out. Presence of a CD99 + small round blue cell tumor and detection of an EWSR1 rearrangement at 22q12 in 84% of cells via FISH testing are consistent with diagnosis of recurrent Ewing's sarcoma.
After that, patient had a CT thorax, abdomen, and pelvis with contrast, showing no evidence of visceral metastases disease. He then proceeded to have a whole‐body SPECT and whole‐body PET FDG, showing single brain metastases with elevated activity in left skull base region and no evidence to suggest extracranial or bone metastases elsewhere Figures 1, 2.
FIGURE 1 Axial MRI images A (T1W), B (T2W), C (T2 PROPELLER), D (FSPGR), and E (Diffusion weighted) demonstrating 7 cm by 4 cm lesion which consists of solid and cystic components with surrounding edema. Mass effect of the lesion causes midline shift of 6 mm to the right
FIGURE 2 Sagittal (A) and coronal (B) MRI images demonstrating lesion in left temporal lobe eroding through base of skull with extracranial extension in the infratemporal fossa. Lesion extends up to pterygoid plates and posterior superior nasopharynx on the left side
2.3 Outcome and follow‐up
The patient was then referred back to the initial oncology department for further management. At time of writing this report, the patient has had five courses of chemotherapy, ifosfamide, and etoposide (Doxifos) and had an MRI showing shrinkage of tumor by more than 50% after second course of chemotherapy. He will be continued with more courses of Doxifos and possible surgical resection Figures 3 and 4.
FIGURE 3 Dramatic regression of both intracranial and extracranial components of tumor is seen after chemotherapy. Comparison of images before chemotherapy (right) and after chemotherapy (left) are seen in A (axial view), B (sagittal view) and C (coronal view)
FIGURE 4 Figure illustrating chronological order of patient's disease and progression
3 DISCUSSION
Ewing's sarcoma is a very rare type of bone or soft tissue tumor, predominantly affecting children, adolescents, and young adult. It is the however the second most common type of malignant bone tumors after osteosarcoma. The annual incidence of Ewing's sarcoma is around 1.8 per million for age 0‐14 and 3.7 per million for age 15‐24. The incidence rate is highest among the 15‐19 age group, which is 4.8 per million per year. It is also more commonly seen in male as compared to female with a ratio of 1.89:1.
1
Ewing's sarcoma is more common among Caucasians as compared to the other races.
2
,
3
,
4
Our patient, a 17‐year‐old Caucasian male at time of discovery, would fit into the category of highest incidence. Due to rarity of disease, the cause of Ewing's sarcoma is still unknown as most of the cases appear sporadically. Studies have shown that the t(11;22)(q24;q12) translocation is found in about 85% of Ewing's sarcoma, which leads to an EWS/FLI1 fusion gene but more studies have to be done to further understand the significance.
5
It is in fact one of the most aggressive cancer with high metastatic potential.
6
On first discovery of right pelvic Ewing's sarcoma 7 years ago, our patient had undergone a hemipelvectomy, coupled with a regimen of neo‐adjuvant chemotherapy, 25 sessions of radiotherapy, and a regimen of adjuvant chemotherapy. In fact, studies on pelvic Ewing's sarcoma have shown that surgery coupled with neo‐adjuvant chemotherapy and radiotherapy would produce better outcome as compared to radiotherapy coupled with neo‐adjuvant chemotherapy or radiotherapy alone.
7
,
8
,
9
,
10
,
11
,
12
,
13
However, the results could be biased due to the fact that smaller sized tumors were managed surgically while large tumors were managed with neo‐adjuvant chemotherapy and radiotherapy. It is also seen that neo‐adjuvant chemotherapy would provide benefit on local control as compared to surgery with radiotherapy alone.
14
Before surgical resection, our patient had neo‐adjuvant chemotherapy. He had undergone of 8 cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) chemotherapy regime. VIDE chemotherapy is widely used across Europe in management of Ewing's sarcoma as it is considered the most effective treatment. It is also associated with low rate of adverse reactions. Our patient had an episode of neutropenia‐related fever during the course of VIDE, which is seen in 65.8% of the patients receiving this chemotherapy regimen.
15
After 8 courses of VIDE, our patient had 25 courses of neo‐adjuvant radiotherapy, followed by surgical resection. He was then further managed with another 8 cycles of adjuvant chemotherapy. This chemotherapy regimen includes vincristine, actinomycin D or also known as dactinomycin, and ifosfamide (VAI). VAI is one of the most commonly used consolidation regimen. In fact, few studies and trial had been carried out to study on replacement of ifosfamide with cyclophosphamide due to the higher modifications needed for VAI; however, both of them were found to have similar efficacy.
16
,
17
There are also ongoing studies on different chemotherapy agents that could be incorporated in consolidation regimen for Ewing's sarcoma including doxorubicin, busulfan, mephalan, or even zoledronic acid.
18
,
19
,
20
After 6 years of complete remission, our patient had an episode of collapse and was found to develop secondary brain metastasis. Brain metastasis is rare among children with solid tumors, usually presenting with seizure or hemiparesis.
21
However, Ewing's sarcoma is the most common tumor causing secondary brain metastasis.
22
,
23
This might be due to the consequence of chemotherapy effectively suppressing systemic metastases while leaving the central nervous vulnerable due to blood‐brain barrier.
24
A study of 335 Ewing's sarcoma patients shows that only 3.3% had brain metastases.
25
Another study of 80 children with Ewing's sarcoma shows higher rate of 8.8% with secondary brain metastases.
21
Due to the fact that Ewing's sarcoma is one of the commonest childhood tumor to develop brain metastases, prophylactic central nervous system irradiation and intrathecal methotrexate as part of initial therapy had been advocated in management of newly diagnosed Ewing's sarcoma in the past to prevent occurrence of central nervous system Ewing's sarcoma. However, the overall risk of secondary brain metastases was the same; hence, current regimens do not include these measures.
26
The overall survival rate of secondary brain metastasis from Ewing's sarcoma is grave, usually with a period of 2 months from time of brain metastasis which improved to 7 months on surgical resection.
22
,
27
,
28
However, two cases of long‐term survival were reported. They had combination of surgical resection, chemotherapy, and radiotherapy.
25
,
29
The literature on secondary brain metastases from Ewing's sarcoma is scarce. Most of them are focused on children with very minimal literature on young adults. This might be due to the fact that patients could be asymptomatic or present with minor symptoms such as headache.
30
Further research or study is definitely required.
This paper puts forward a proposal for routine imaging such as MRI scan of head on follow‐up of patient with Ewing's sarcoma. Firstly, this might provide a more accurate understanding on the incidence of secondary brain metastases in Ewing's sarcoma. Secondly, this could help in diagnosing any brain metastases before the tumor grows large. Thirdly, this could improve the outcome by enabling surgical resection coupled with chemotherapy or radiotherapy when the tumor is small.
This case serves to improve our understanding toward the rare occurrence of secondary brain metastases of Ewing's sarcoma after long period of complete remission, as well as highlighting the importance of further study and research in this field. Routine brain imaging on follow‐up of patient with Ewing's sarcoma could be the next step forward in improving our understanding of this disease as well as improving long‐term outcome of patients.
Learning points
Ewing's sarcoma is the most common childhood tumor to cause secondary brain metastasis.
22
,
23
Surgical resection coupled with chemotherapy and radiotherapy provides the best long‐term outcome in management of primary or secondary Ewing's sarcoma.
Routine brain imaging and long‐term follow‐up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long‐term outcome for patients.
CONFLICT OF INTEREST
The author of this study has no conflict of interest to declare.
AUTHORS’ CONTRIBUTION
JZP: Conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, and critical revision for important intellectual content.
ETHICAL APPROVAL
No approval is required.
Supporting information
App S1
Click here for additional data file.
ACKNOWLEDGMENTS
The author would like to acknowledge the patient for providing consent to share his case. The author would also like to acknowledge the histopathologist and radiologist of Sheffield Teaching Hospital for their contribution. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
Data are available in article supplementary material. | RECEIVED 8 CYCLES | DrugDosageText | CC BY | 33489215 | 18,933,287 | 2021-01 |
What was the dosage of drug 'VINCRISTINE SULFATE'? | Secondary brain metastases of Ewing's sarcoma presenting with collapse after 6 years of complete remission.
Routine brain imaging with MRI and long-term follow-up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long-term outcome for patients.
1 INTRODUCTION
A 23‐year‐old gentleman came to Emergency Department with first episode of sudden collapse. He had a right pelvic Ewing's sarcoma surgically resected 6 years ago. MRI of the head demonstrated a lesion in right temporal lobe, extending into infratemporal fossa. He was referred to oncology for further management with chemotherapy.
Ewing's sarcoma is a childhood tumor which is rarely seen, occurring in 2.93 children per 1 000 000, more common in male and hardly understood by many clinicians. The definite diagnosis is of Ewing's sarcoma is usually made in tertiary hospital via biopsy and microscopic evaluation of tumor cells and molecular analysis. Ewing's sarcoma usually requires treatment from different specialties including pediatric or adult oncologist, orthopedic surgeons, and other specialists depending on tumor site. Management of Ewing's sarcoma varies greatly among different patients but includes chemotherapy, radiotherapy, and surgical resection. Most of the brain metastases from Ewing's sarcoma usually occur in the range of 20‐30 months from the time of diagnosis of primary tumor. This case report describes the rare presentation of a gentleman who develops single secondary brain metastases of Ewing's sarcoma after 6 years of complete remission.
2 CASE HISTORY
A 23‐year‐old Caucasian gentleman was brought into the Emergency Department after an episode of collapse with loss of consciousness for 2 minutes. Up‐rolling of both eyeballs was seen throughout the episode.
He had been having 2 months history of intermittent pain around left temporomandibular area, not relieved by any analgesics. He had previous history of Ewing's sarcoma found in his right pelvis on May 2013. It was surgically removed via hemipelvectomy on January 2014. Postoperatively, he was continued with 16 courses of chemotherapy and 25 sessions of radiotherapy in total. He was then followed up by oncology department every 6 months for 4 year, followed by annually for 2 years. A chest and pelvic X‐ray was done before every appointment. He was discharged from follow‐up on Jan 2020 disease‐free. Apart from that, he had no other medical or surgical condition.
2.1 Examination
On physical examination, patient was alert and well orientated with Glasgow Coma Scale of 15/15. There was a small bruise to right side of temple with no laceration, possibly due to the collapse. No swelling or tenderness upon palpation was felt on the left side of the face. Upon cranial nerve examination, the only positive sign was a horizontal nystagmus seen in both eyes. There was also no abnormality noted in sensory and motor neurological examination of bilateral upper and lower limbs.
2.2 Investigations
Routine blood test including full blood count, urea and electrolyte, and C‐reactive protein was performed. No abnormality or raised inflammatory marker was noted.
Computed tomography scan of the head was requested. A space occupying lesion at the left temporal lobe extending through the skull base to the left masticator space was found. This warranted for a further contrast‐enhanced magnetic resonance imaging (MRI) of the head. An aggressive large mass lesion measuring 7 cm by 4 cm was seen in the left temporal location, eroding through the skull base, resulting in extracranial component in the infratemporal fossa. It had solid and cystic components with surrounding edema. Medially, the lesion was seen to extend up to the pterygoid plates and the posterior superior nasopharynx on the left side, and a resultant block of the Eustachian tube and a left mastoid effusion was seen. Midline shift to the right of 6mm as a result of mass effect was also noted. CT‐guided biopsy of the left superficial temporal fossa lesion was carried out. Presence of a CD99 + small round blue cell tumor and detection of an EWSR1 rearrangement at 22q12 in 84% of cells via FISH testing are consistent with diagnosis of recurrent Ewing's sarcoma.
After that, patient had a CT thorax, abdomen, and pelvis with contrast, showing no evidence of visceral metastases disease. He then proceeded to have a whole‐body SPECT and whole‐body PET FDG, showing single brain metastases with elevated activity in left skull base region and no evidence to suggest extracranial or bone metastases elsewhere Figures 1, 2.
FIGURE 1 Axial MRI images A (T1W), B (T2W), C (T2 PROPELLER), D (FSPGR), and E (Diffusion weighted) demonstrating 7 cm by 4 cm lesion which consists of solid and cystic components with surrounding edema. Mass effect of the lesion causes midline shift of 6 mm to the right
FIGURE 2 Sagittal (A) and coronal (B) MRI images demonstrating lesion in left temporal lobe eroding through base of skull with extracranial extension in the infratemporal fossa. Lesion extends up to pterygoid plates and posterior superior nasopharynx on the left side
2.3 Outcome and follow‐up
The patient was then referred back to the initial oncology department for further management. At time of writing this report, the patient has had five courses of chemotherapy, ifosfamide, and etoposide (Doxifos) and had an MRI showing shrinkage of tumor by more than 50% after second course of chemotherapy. He will be continued with more courses of Doxifos and possible surgical resection Figures 3 and 4.
FIGURE 3 Dramatic regression of both intracranial and extracranial components of tumor is seen after chemotherapy. Comparison of images before chemotherapy (right) and after chemotherapy (left) are seen in A (axial view), B (sagittal view) and C (coronal view)
FIGURE 4 Figure illustrating chronological order of patient's disease and progression
3 DISCUSSION
Ewing's sarcoma is a very rare type of bone or soft tissue tumor, predominantly affecting children, adolescents, and young adult. It is the however the second most common type of malignant bone tumors after osteosarcoma. The annual incidence of Ewing's sarcoma is around 1.8 per million for age 0‐14 and 3.7 per million for age 15‐24. The incidence rate is highest among the 15‐19 age group, which is 4.8 per million per year. It is also more commonly seen in male as compared to female with a ratio of 1.89:1.
1
Ewing's sarcoma is more common among Caucasians as compared to the other races.
2
,
3
,
4
Our patient, a 17‐year‐old Caucasian male at time of discovery, would fit into the category of highest incidence. Due to rarity of disease, the cause of Ewing's sarcoma is still unknown as most of the cases appear sporadically. Studies have shown that the t(11;22)(q24;q12) translocation is found in about 85% of Ewing's sarcoma, which leads to an EWS/FLI1 fusion gene but more studies have to be done to further understand the significance.
5
It is in fact one of the most aggressive cancer with high metastatic potential.
6
On first discovery of right pelvic Ewing's sarcoma 7 years ago, our patient had undergone a hemipelvectomy, coupled with a regimen of neo‐adjuvant chemotherapy, 25 sessions of radiotherapy, and a regimen of adjuvant chemotherapy. In fact, studies on pelvic Ewing's sarcoma have shown that surgery coupled with neo‐adjuvant chemotherapy and radiotherapy would produce better outcome as compared to radiotherapy coupled with neo‐adjuvant chemotherapy or radiotherapy alone.
7
,
8
,
9
,
10
,
11
,
12
,
13
However, the results could be biased due to the fact that smaller sized tumors were managed surgically while large tumors were managed with neo‐adjuvant chemotherapy and radiotherapy. It is also seen that neo‐adjuvant chemotherapy would provide benefit on local control as compared to surgery with radiotherapy alone.
14
Before surgical resection, our patient had neo‐adjuvant chemotherapy. He had undergone of 8 cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) chemotherapy regime. VIDE chemotherapy is widely used across Europe in management of Ewing's sarcoma as it is considered the most effective treatment. It is also associated with low rate of adverse reactions. Our patient had an episode of neutropenia‐related fever during the course of VIDE, which is seen in 65.8% of the patients receiving this chemotherapy regimen.
15
After 8 courses of VIDE, our patient had 25 courses of neo‐adjuvant radiotherapy, followed by surgical resection. He was then further managed with another 8 cycles of adjuvant chemotherapy. This chemotherapy regimen includes vincristine, actinomycin D or also known as dactinomycin, and ifosfamide (VAI). VAI is one of the most commonly used consolidation regimen. In fact, few studies and trial had been carried out to study on replacement of ifosfamide with cyclophosphamide due to the higher modifications needed for VAI; however, both of them were found to have similar efficacy.
16
,
17
There are also ongoing studies on different chemotherapy agents that could be incorporated in consolidation regimen for Ewing's sarcoma including doxorubicin, busulfan, mephalan, or even zoledronic acid.
18
,
19
,
20
After 6 years of complete remission, our patient had an episode of collapse and was found to develop secondary brain metastasis. Brain metastasis is rare among children with solid tumors, usually presenting with seizure or hemiparesis.
21
However, Ewing's sarcoma is the most common tumor causing secondary brain metastasis.
22
,
23
This might be due to the consequence of chemotherapy effectively suppressing systemic metastases while leaving the central nervous vulnerable due to blood‐brain barrier.
24
A study of 335 Ewing's sarcoma patients shows that only 3.3% had brain metastases.
25
Another study of 80 children with Ewing's sarcoma shows higher rate of 8.8% with secondary brain metastases.
21
Due to the fact that Ewing's sarcoma is one of the commonest childhood tumor to develop brain metastases, prophylactic central nervous system irradiation and intrathecal methotrexate as part of initial therapy had been advocated in management of newly diagnosed Ewing's sarcoma in the past to prevent occurrence of central nervous system Ewing's sarcoma. However, the overall risk of secondary brain metastases was the same; hence, current regimens do not include these measures.
26
The overall survival rate of secondary brain metastasis from Ewing's sarcoma is grave, usually with a period of 2 months from time of brain metastasis which improved to 7 months on surgical resection.
22
,
27
,
28
However, two cases of long‐term survival were reported. They had combination of surgical resection, chemotherapy, and radiotherapy.
25
,
29
The literature on secondary brain metastases from Ewing's sarcoma is scarce. Most of them are focused on children with very minimal literature on young adults. This might be due to the fact that patients could be asymptomatic or present with minor symptoms such as headache.
30
Further research or study is definitely required.
This paper puts forward a proposal for routine imaging such as MRI scan of head on follow‐up of patient with Ewing's sarcoma. Firstly, this might provide a more accurate understanding on the incidence of secondary brain metastases in Ewing's sarcoma. Secondly, this could help in diagnosing any brain metastases before the tumor grows large. Thirdly, this could improve the outcome by enabling surgical resection coupled with chemotherapy or radiotherapy when the tumor is small.
This case serves to improve our understanding toward the rare occurrence of secondary brain metastases of Ewing's sarcoma after long period of complete remission, as well as highlighting the importance of further study and research in this field. Routine brain imaging on follow‐up of patient with Ewing's sarcoma could be the next step forward in improving our understanding of this disease as well as improving long‐term outcome of patients.
Learning points
Ewing's sarcoma is the most common childhood tumor to cause secondary brain metastasis.
22
,
23
Surgical resection coupled with chemotherapy and radiotherapy provides the best long‐term outcome in management of primary or secondary Ewing's sarcoma.
Routine brain imaging and long‐term follow‐up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long‐term outcome for patients.
CONFLICT OF INTEREST
The author of this study has no conflict of interest to declare.
AUTHORS’ CONTRIBUTION
JZP: Conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, and critical revision for important intellectual content.
ETHICAL APPROVAL
No approval is required.
Supporting information
App S1
Click here for additional data file.
ACKNOWLEDGMENTS
The author would like to acknowledge the patient for providing consent to share his case. The author would also like to acknowledge the histopathologist and radiologist of Sheffield Teaching Hospital for their contribution. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
Data are available in article supplementary material. | UNK, CYCLIC (8 COURSES OF VIDE) | DrugDosageText | CC BY | 33489215 | 18,898,550 | 2021-01 |
What was the outcome of reaction 'Neoplasm progression'? | Secondary brain metastases of Ewing's sarcoma presenting with collapse after 6 years of complete remission.
Routine brain imaging with MRI and long-term follow-up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long-term outcome for patients.
1 INTRODUCTION
A 23‐year‐old gentleman came to Emergency Department with first episode of sudden collapse. He had a right pelvic Ewing's sarcoma surgically resected 6 years ago. MRI of the head demonstrated a lesion in right temporal lobe, extending into infratemporal fossa. He was referred to oncology for further management with chemotherapy.
Ewing's sarcoma is a childhood tumor which is rarely seen, occurring in 2.93 children per 1 000 000, more common in male and hardly understood by many clinicians. The definite diagnosis is of Ewing's sarcoma is usually made in tertiary hospital via biopsy and microscopic evaluation of tumor cells and molecular analysis. Ewing's sarcoma usually requires treatment from different specialties including pediatric or adult oncologist, orthopedic surgeons, and other specialists depending on tumor site. Management of Ewing's sarcoma varies greatly among different patients but includes chemotherapy, radiotherapy, and surgical resection. Most of the brain metastases from Ewing's sarcoma usually occur in the range of 20‐30 months from the time of diagnosis of primary tumor. This case report describes the rare presentation of a gentleman who develops single secondary brain metastases of Ewing's sarcoma after 6 years of complete remission.
2 CASE HISTORY
A 23‐year‐old Caucasian gentleman was brought into the Emergency Department after an episode of collapse with loss of consciousness for 2 minutes. Up‐rolling of both eyeballs was seen throughout the episode.
He had been having 2 months history of intermittent pain around left temporomandibular area, not relieved by any analgesics. He had previous history of Ewing's sarcoma found in his right pelvis on May 2013. It was surgically removed via hemipelvectomy on January 2014. Postoperatively, he was continued with 16 courses of chemotherapy and 25 sessions of radiotherapy in total. He was then followed up by oncology department every 6 months for 4 year, followed by annually for 2 years. A chest and pelvic X‐ray was done before every appointment. He was discharged from follow‐up on Jan 2020 disease‐free. Apart from that, he had no other medical or surgical condition.
2.1 Examination
On physical examination, patient was alert and well orientated with Glasgow Coma Scale of 15/15. There was a small bruise to right side of temple with no laceration, possibly due to the collapse. No swelling or tenderness upon palpation was felt on the left side of the face. Upon cranial nerve examination, the only positive sign was a horizontal nystagmus seen in both eyes. There was also no abnormality noted in sensory and motor neurological examination of bilateral upper and lower limbs.
2.2 Investigations
Routine blood test including full blood count, urea and electrolyte, and C‐reactive protein was performed. No abnormality or raised inflammatory marker was noted.
Computed tomography scan of the head was requested. A space occupying lesion at the left temporal lobe extending through the skull base to the left masticator space was found. This warranted for a further contrast‐enhanced magnetic resonance imaging (MRI) of the head. An aggressive large mass lesion measuring 7 cm by 4 cm was seen in the left temporal location, eroding through the skull base, resulting in extracranial component in the infratemporal fossa. It had solid and cystic components with surrounding edema. Medially, the lesion was seen to extend up to the pterygoid plates and the posterior superior nasopharynx on the left side, and a resultant block of the Eustachian tube and a left mastoid effusion was seen. Midline shift to the right of 6mm as a result of mass effect was also noted. CT‐guided biopsy of the left superficial temporal fossa lesion was carried out. Presence of a CD99 + small round blue cell tumor and detection of an EWSR1 rearrangement at 22q12 in 84% of cells via FISH testing are consistent with diagnosis of recurrent Ewing's sarcoma.
After that, patient had a CT thorax, abdomen, and pelvis with contrast, showing no evidence of visceral metastases disease. He then proceeded to have a whole‐body SPECT and whole‐body PET FDG, showing single brain metastases with elevated activity in left skull base region and no evidence to suggest extracranial or bone metastases elsewhere Figures 1, 2.
FIGURE 1 Axial MRI images A (T1W), B (T2W), C (T2 PROPELLER), D (FSPGR), and E (Diffusion weighted) demonstrating 7 cm by 4 cm lesion which consists of solid and cystic components with surrounding edema. Mass effect of the lesion causes midline shift of 6 mm to the right
FIGURE 2 Sagittal (A) and coronal (B) MRI images demonstrating lesion in left temporal lobe eroding through base of skull with extracranial extension in the infratemporal fossa. Lesion extends up to pterygoid plates and posterior superior nasopharynx on the left side
2.3 Outcome and follow‐up
The patient was then referred back to the initial oncology department for further management. At time of writing this report, the patient has had five courses of chemotherapy, ifosfamide, and etoposide (Doxifos) and had an MRI showing shrinkage of tumor by more than 50% after second course of chemotherapy. He will be continued with more courses of Doxifos and possible surgical resection Figures 3 and 4.
FIGURE 3 Dramatic regression of both intracranial and extracranial components of tumor is seen after chemotherapy. Comparison of images before chemotherapy (right) and after chemotherapy (left) are seen in A (axial view), B (sagittal view) and C (coronal view)
FIGURE 4 Figure illustrating chronological order of patient's disease and progression
3 DISCUSSION
Ewing's sarcoma is a very rare type of bone or soft tissue tumor, predominantly affecting children, adolescents, and young adult. It is the however the second most common type of malignant bone tumors after osteosarcoma. The annual incidence of Ewing's sarcoma is around 1.8 per million for age 0‐14 and 3.7 per million for age 15‐24. The incidence rate is highest among the 15‐19 age group, which is 4.8 per million per year. It is also more commonly seen in male as compared to female with a ratio of 1.89:1.
1
Ewing's sarcoma is more common among Caucasians as compared to the other races.
2
,
3
,
4
Our patient, a 17‐year‐old Caucasian male at time of discovery, would fit into the category of highest incidence. Due to rarity of disease, the cause of Ewing's sarcoma is still unknown as most of the cases appear sporadically. Studies have shown that the t(11;22)(q24;q12) translocation is found in about 85% of Ewing's sarcoma, which leads to an EWS/FLI1 fusion gene but more studies have to be done to further understand the significance.
5
It is in fact one of the most aggressive cancer with high metastatic potential.
6
On first discovery of right pelvic Ewing's sarcoma 7 years ago, our patient had undergone a hemipelvectomy, coupled with a regimen of neo‐adjuvant chemotherapy, 25 sessions of radiotherapy, and a regimen of adjuvant chemotherapy. In fact, studies on pelvic Ewing's sarcoma have shown that surgery coupled with neo‐adjuvant chemotherapy and radiotherapy would produce better outcome as compared to radiotherapy coupled with neo‐adjuvant chemotherapy or radiotherapy alone.
7
,
8
,
9
,
10
,
11
,
12
,
13
However, the results could be biased due to the fact that smaller sized tumors were managed surgically while large tumors were managed with neo‐adjuvant chemotherapy and radiotherapy. It is also seen that neo‐adjuvant chemotherapy would provide benefit on local control as compared to surgery with radiotherapy alone.
14
Before surgical resection, our patient had neo‐adjuvant chemotherapy. He had undergone of 8 cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) chemotherapy regime. VIDE chemotherapy is widely used across Europe in management of Ewing's sarcoma as it is considered the most effective treatment. It is also associated with low rate of adverse reactions. Our patient had an episode of neutropenia‐related fever during the course of VIDE, which is seen in 65.8% of the patients receiving this chemotherapy regimen.
15
After 8 courses of VIDE, our patient had 25 courses of neo‐adjuvant radiotherapy, followed by surgical resection. He was then further managed with another 8 cycles of adjuvant chemotherapy. This chemotherapy regimen includes vincristine, actinomycin D or also known as dactinomycin, and ifosfamide (VAI). VAI is one of the most commonly used consolidation regimen. In fact, few studies and trial had been carried out to study on replacement of ifosfamide with cyclophosphamide due to the higher modifications needed for VAI; however, both of them were found to have similar efficacy.
16
,
17
There are also ongoing studies on different chemotherapy agents that could be incorporated in consolidation regimen for Ewing's sarcoma including doxorubicin, busulfan, mephalan, or even zoledronic acid.
18
,
19
,
20
After 6 years of complete remission, our patient had an episode of collapse and was found to develop secondary brain metastasis. Brain metastasis is rare among children with solid tumors, usually presenting with seizure or hemiparesis.
21
However, Ewing's sarcoma is the most common tumor causing secondary brain metastasis.
22
,
23
This might be due to the consequence of chemotherapy effectively suppressing systemic metastases while leaving the central nervous vulnerable due to blood‐brain barrier.
24
A study of 335 Ewing's sarcoma patients shows that only 3.3% had brain metastases.
25
Another study of 80 children with Ewing's sarcoma shows higher rate of 8.8% with secondary brain metastases.
21
Due to the fact that Ewing's sarcoma is one of the commonest childhood tumor to develop brain metastases, prophylactic central nervous system irradiation and intrathecal methotrexate as part of initial therapy had been advocated in management of newly diagnosed Ewing's sarcoma in the past to prevent occurrence of central nervous system Ewing's sarcoma. However, the overall risk of secondary brain metastases was the same; hence, current regimens do not include these measures.
26
The overall survival rate of secondary brain metastasis from Ewing's sarcoma is grave, usually with a period of 2 months from time of brain metastasis which improved to 7 months on surgical resection.
22
,
27
,
28
However, two cases of long‐term survival were reported. They had combination of surgical resection, chemotherapy, and radiotherapy.
25
,
29
The literature on secondary brain metastases from Ewing's sarcoma is scarce. Most of them are focused on children with very minimal literature on young adults. This might be due to the fact that patients could be asymptomatic or present with minor symptoms such as headache.
30
Further research or study is definitely required.
This paper puts forward a proposal for routine imaging such as MRI scan of head on follow‐up of patient with Ewing's sarcoma. Firstly, this might provide a more accurate understanding on the incidence of secondary brain metastases in Ewing's sarcoma. Secondly, this could help in diagnosing any brain metastases before the tumor grows large. Thirdly, this could improve the outcome by enabling surgical resection coupled with chemotherapy or radiotherapy when the tumor is small.
This case serves to improve our understanding toward the rare occurrence of secondary brain metastases of Ewing's sarcoma after long period of complete remission, as well as highlighting the importance of further study and research in this field. Routine brain imaging on follow‐up of patient with Ewing's sarcoma could be the next step forward in improving our understanding of this disease as well as improving long‐term outcome of patients.
Learning points
Ewing's sarcoma is the most common childhood tumor to cause secondary brain metastasis.
22
,
23
Surgical resection coupled with chemotherapy and radiotherapy provides the best long‐term outcome in management of primary or secondary Ewing's sarcoma.
Routine brain imaging and long‐term follow‐up of Ewing's sarcoma could be the way to move forward by increasing our understanding in this area, as well as improving treatment and long‐term outcome for patients.
CONFLICT OF INTEREST
The author of this study has no conflict of interest to declare.
AUTHORS’ CONTRIBUTION
JZP: Conception and design, acquisition of data, analysis and interpretation of data, drafting of manuscript, and critical revision for important intellectual content.
ETHICAL APPROVAL
No approval is required.
Supporting information
App S1
Click here for additional data file.
ACKNOWLEDGMENTS
The author would like to acknowledge the patient for providing consent to share his case. The author would also like to acknowledge the histopathologist and radiologist of Sheffield Teaching Hospital for their contribution. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
Data are available in article supplementary material. | Recovering | ReactionOutcome | CC BY | 33489215 | 18,907,873 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Alopecia'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epidermal necrosis'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nail toxicity'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Onycholysis'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palmar-plantar erythrodysaesthesia syndrome'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin exfoliation'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin haemorrhage'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin lesion'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin ulcer'. | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | LETROZOLE, PACLITAXEL | DrugsGivenReaction | CC BY | 33489227 | 18,618,573 | 2021-01 |
What is the weight of the patient? | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | 70 kg. | Weight | CC BY | 33489227 | 18,618,573 | 2021-01 |
What was the administration route of drug 'PACLITAXEL'? | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33489227 | 18,618,573 | 2021-01 |
What was the outcome of reaction 'Alopecia'? | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | Recovered | ReactionOutcome | CC BY | 33489227 | 18,618,573 | 2021-01 |
What was the outcome of reaction 'Nail toxicity'? | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | Recovered | ReactionOutcome | CC BY | 33489227 | 18,618,573 | 2021-01 |
What was the outcome of reaction 'Palmar-plantar erythrodysaesthesia syndrome'? | An unusual and severe case of paclitaxel-induced hand-foot syndrome.
Although paclitaxel is known to cause mild skin toxicity, it may induce severe HFS requiring drug withdrawal. Patients with high disease burden might receive prolonged paclitaxel chemotherapy. Hence, a grade 2 toxicity would better indicate withdrawal of paclitaxel instead of suspension and rechallenge, to prevent such severe HFS requiring long-time recovery.
1 COMMENT
Although paclitaxel is known to induce skin adverse events, acral erythema has been described only in few case reports.
1
We herein report the case of a 44‐year‐old premenopausal female patient who was referred to our department for metastatic breast cancer. She had a history of acute coronary syndrome 9 months earlier receiving bisprolol 2.5 mg daily, aspirin, and atorvastatin. The pathology report showed mixed ductal‐lobular invasive carcinoma, HER2 negative, hormone receptor‐positive. Staging workup revealed multiple metastases in the liver with diffuse peritoneal carcinosis. As anthracyclines were contraindicated, first‐line weekly paclitaxel at a dose of 80 mg/m2 was initiated. Over nine courses, the patient had a complete peritoneal response and partial response to hepatic lesions. Main toxicities were mild ungueal toxicity and alopecia. Maintenance therapy with letrozole was carried out for 4 months. The patient presented then liver disease progression with abundant ascites. Weekly paclitaxel was reintroduced at the same dose with premedication before each infusion (corticosteroids, anti‐H1, and setrons). After six infusions, the patient presented WHO grade 2, hand‐foot syndrome, which resolved 2 weeks after chemotherapy discontinuation. Paclitaxel was reintroduced with preventive topical emollients and a 20% dose reduction. After three other courses, the patient presented erythematous and violaceous lesions of her palms (Figure 1) and multiple ulcerations and epidermal necrolysis of the dorsum of her foot (Figure 2) associated with severe peeling soles and bleeding (Figures 3 and 4). The patient was referred to the dermatology department, where analgesics, emollients, topical steroids, and antibiotics were prescribed. Paclitaxel was then withdrawn. Three weeks later, the patient died due to disease progression, as no other chemotherapy could be initiated.
FIGURE 1 Erythematous and violaceous lesions induced by paclitaxel
FIGURE 2 Paclitaxel‐induced ulcerations and epidermal necrosis of the dorsum of the foot
FIGURE 3 Paclitaxel‐induced severe peeling feet
FIGURE 4 Paclitaxel‐induced peeling, bleeding, and onycholysis
CONFLICT OF INTEREST
None declared.
AUTHORS' CONTRIBUTION
IBA: collected the patient's data and drafted the manuscript. SBN, AZ, JA, and SF: revised the manuscript and gave critical review of the content. AH and MB: gave approval for the final version to be published after review.
ETHICAL APPROVAL
The patient gave verbal and written consent for the publication of these clinical images.
ACKNOWLEDGMENTS
We thank the dermatologists of the military hospital of Tunis for delivering best supportive care for this patient.
DATA AVAILABILITY STATEMENT
The patient's records are available from the corresponding author. | Recovered | ReactionOutcome | CC BY | 33489227 | 18,618,573 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infusion related reaction'. | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | CETUXIMAB, CHLORPHENIRAMINE MALEATE, DEXAMETHASONE SODIUM PHOSPHATE, FAMOTIDINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN, PANITUMUMAB | DrugsGivenReaction | CC BY | 33489709 | 19,306,605 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | CETUXIMAB, DEXAMETHASONE SODIUM PHOSPHATE, FAMOTIDINE, FLUOROURACIL, LEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY | 33489709 | 19,230,934 | 2021-01 |
What was the administration route of drug 'CETUXIMAB'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | Other | DrugAdministrationRoute | CC BY | 33489709 | 19,306,605 | 2021-01 |
What was the administration route of drug 'PANITUMUMAB'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | Intravenous drip | DrugAdministrationRoute | CC BY | 33489709 | 19,306,605 | 2021-01 |
What was the dosage of drug 'CHLORPHENIRAMINE MALEATE'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | 5 mg (milligrams). | DrugDosage | CC BY | 33489709 | 19,306,605 | 2021-01 |
What was the dosage of drug 'DEXAMETHASONE'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | 1.65 mg (milligrams). | DrugDosage | CC BY | 33489709 | 19,247,283 | 2021-01 |
What was the dosage of drug 'LEUCOVORIN CALCIUM'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | 7 CYCLIC | DrugDosageText | CC BY | 33489709 | 19,230,934 | 2021-01 |
What was the dosage of drug 'LEUCOVORIN'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | MFOLFOX6 REGIMEN | DrugDosageText | CC BY | 33489709 | 19,306,605 | 2021-01 |
What was the dosage of drug 'LORATADINE'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | 50 mg (milligrams). | DrugDosage | CC BY | 33489709 | 19,247,283 | 2021-01 |
What was the outcome of reaction 'Infusion related reaction'? | Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.
Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.
Introduction
Cetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].
We herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.
Case report
A 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)
Fig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated
Discussion
Monoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].
IR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].
Our study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.
To our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Compliance With Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
Research involving human participants and/or animals
Formal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
Informed consent was obtained from the individual who participated in the study. | Recovered | ReactionOutcome | CC BY | 33489709 | 19,306,605 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory failure'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bone marrow failure'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Brain herniation'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'C-reactive protein increased'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac ventricular thrombosis'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral haemorrhage'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebrovascular disorder'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Embolism'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Endocarditis'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Full blood count decreased'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal injury'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Heart injury'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intracranial pressure increased'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver injury'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Muscle injury'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
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