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Abstract

Patients with cancer have a higher risk of severe COVID-19, and expert consensus advocates for COVID-19 vaccination in this population. Some cases of autoimmune hepatitis have been described after the administration of COVID-19 vaccine in the people in apparently good health. Immune checkpoint inhibitors (ICIs) are responsible for a wide spectrum of immune-related adverse events (irAEs). This article reports a case of hepatitis and colitis in a 52-year-old woman who was undergoing immunotherapy and was HBV positive 10 days after receiving the first Pfizer-BioNTech COVID-19 vaccine dose. Because both ICIs and the COVID-19 vaccines stimulate the immune response, the authors hypothesize that these vaccines may increase the incidence of irAEs during ICI treatment. There is a complex interplay between the immune-mediated reaction triggered by the vaccination and PD-L1 co-administration.

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Objectives During the summer of 2021, case reports began to emerge documenting a small number of individuals who developed autoimmune hepatitis (AIH) following COVID-19 vaccination. These cases are rare and novel, and very little is known. In our systematic review, we analyzed every published case of AIH and reviewed their characteristic findings, treatment, and outcomes. Methods We searched PubMed, Embase, and Web of Science from December 1, 2019, to November 1, 2021. Two researchers independently extracted information from the articles about vaccine type, patient history, laboratory values, histology results, treatment regimens, and disease course. Results Thirty-two patients developed AIH-like syndromes after receiving a COVID-19 vaccine. Jaundice was the most frequently reported symptom (81%), and 19% of patients were initially asymptomatic and presented with elevated liver enzymes found during routine bloodwork. Mean alanine transaminase, aspartate transaminase, and total bilirubin were 1231 U/L, 921 U/L, and 14 mg/dL, respectively. Anti-nuclear antibody was positive in 56%, and anti-smooth muscle antibody in 28% of patients. Steroids were used in 75% of patients. Improvement or complete resolution was seen in 97% of patients. One patient died despite aggressive steroid treatment. Conclusion COVID-19 vaccine-induced AIH is an uncommon association with just 32 documented cases in the literature. Clinicians should be vigilant for AIH in patients who present with liver injury following vaccination. These new findings should under not deter individuals from getting vaccinated, as the benefits of vaccination far outweigh the risks. Fortunately, COVID-19 vaccine-induced AIH appears amendable to corticosteroid therapy and appears to have a favorable outcome.
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Coronavirus disease 2019 (COVID-19) vaccine development and administration have become global priorities since the beginning of the pandemic, particularly for special populations at higher risk of complications and mortality, such as patients with haematologic and solid organ malignancies. This review aims to summarise the current data for COVID-19 vaccine efficacy in patients with cancer, suggest priority areas for future research and look at potential disparities at a global level. Although patients diagnosed with or receiving therapy for cancer were excluded from the initial vaccine trials, emerging evidence now supports vaccine safety with potentially diminished immune response in this group. Several studies that evaluated antibody response to COVID-19 vaccination found that patients with solid malignancies had lower serologic response rates compared to healthy controls, but better than patients with haematologic malignancies, who had the lowest seroconversion rates and antibody titres. As anticipated, poor serologic responses have been particularly observed among patients receiving B-cell depleting therapies. The data on cellular response are scarce and conflicting since not all studies have showed a difference between patients with malignancies and healthy subjects. Several questions concerning vaccination remain unanswered and require further exploration, such as response duration, need for response monitoring and rates of breakthrough infections.
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The development of autoimmune diseases has been reported after SARS-CoV-2 infection. Vaccination against SARS-CoV-2 could also trigger auto-immunity, as it has been described with other vaccines. An aberrant immune response induced by molecular mimicry and bystander activation, especially in predisposed individuals, is a potential mechanism. We report the case of a 76-year-old woman with Hashimoto thyroiditis and prior COVID-19 infection who developed severe autoimmune hepatitis (with typical features including strongly positive anti-smooth muscle antibody and markedly elevated immunoglobulins G, as well as typical histological findings) following SARS-CoV-2 vaccination (mRNA-1273 SARS-CoV-2 vaccine, Moderna®). The link between SARS-CoV-2 vaccination and the development of autoimmune diseases needs to be further investigated. Although a causality relationship cannot be proven, caution may be warranted when vaccinating individuals with known autoimmune diseases.
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Emergency approval of vaccines against COVID-19 provides an opportunity for us to return to pre-pandemic oncology care. However, safety data in cancer patients is lacking due to their exclusion from most phase III trials. We included all patients aged less than 65 years who received a COVID-19 vaccine from 8 December 2020 to 28 February 2021 at our London tertiary oncology centre. Solicited and unsolicited vaccine-related adverse events (VRAEs) were collected using telephone or face-to-face consultation. Within the study period, 373 patients received their first dose of vaccine: Pfizer/BioNTech (75.1%), Oxford/AstraZeneca (23.6%), Moderna (0.3%), and unknown (1.1%). Median follow-up was 25 days (5–85). Median age was 56 years (19–65). Of the patients, 94.9% had a solid malignancy and 76.7% were stage 3–4. The most common cancers were breast (34.0%), lung (13.4%), colorectal (10.2%), and gynaecological (10.2%). Of the patients, 88.5% were receiving anti-cancer treatment (36.2% parenteral chemotherapy and 15.3% immunotherapy), 76.1% developed any grade VRAE of which 2.1% were grade 3. No grade 4/5 or anaphylaxis were observed. The most common VRAEs within 7 days post-vaccination were sore arm (61.7%), fatigue (18.2%), and headaches (12.1%). Most common grade 3 VRAE was fatigue (1.1%). Our results demonstrate that COVID-19 vaccines in oncology patients have mild reactogenicity.
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Background: The efficacy and safety profiles of vaccines against SARS-CoV-2 in patients with cancer is unknown. We aimed to assess the safety and immunogenicity of the BNT162b2 (Pfizer-BioNTech) vaccine in patients with cancer. Methods: For this prospective observational study, we recruited patients with cancer and healthy controls (mostly health-care workers) from three London hospitals between Dec 8, 2020, and Feb 18, 2021. Participants who were vaccinated between Dec 8 and Dec 29, 2020, received two 30 μg doses of BNT162b2 administered intramuscularly 21 days apart; patients vaccinated after this date received only one 30 μg dose with a planned follow-up boost at 12 weeks. Blood samples were taken before vaccination and at 3 weeks and 5 weeks after the first vaccination. Where possible, serial nasopharyngeal real-time RT-PCR (rRT-PCR) swab tests were done every 10 days or in cases of symptomatic COVID-19. The coprimary endpoints were seroconversion to SARS-CoV-2 spike (S) protein in patients with cancer following the first vaccination with the BNT162b2 vaccine and the effect of vaccine boosting after 21 days on seroconversion. All participants with available data were included in the safety and immunogenicity analyses. Ongoing follow-up is underway for further blood sampling after the delayed (12-week) vaccine boost. This study is registered with the NHS Health Research Authority and Health and Care Research Wales (REC ID 20/HRA/2031). Findings: 151 patients with cancer (95 patients with solid cancer and 56 patients with haematological cancer) and 54 healthy controls were enrolled. For this interim data analysis of the safety and immunogenicity of vaccinated patients with cancer, samples and data obtained up to March 19, 2021, were analysed. After exclusion of 17 patients who had been exposed to SARS-CoV-2 (detected by either antibody seroconversion or a positive rRT-PCR COVID-19 swab test) from the immunogenicity analysis, the proportion of positive anti-S IgG titres at approximately 21 days following a single vaccine inoculum across the three cohorts were 32 (94%; 95% CI 81-98) of 34 healthy controls; 21 (38%; 26-51) of 56 patients with solid cancer, and eight (18%; 10-32) of 44 patients with haematological cancer. 16 healthy controls, 25 patients with solid cancer, and six patients with haematological cancer received a second dose on day 21. Of the patients with available blood samples 2 weeks following a 21-day vaccine boost, and excluding 17 participants with evidence of previous natural SARS-CoV-2 exposure, 18 (95%; 95% CI 75-99) of 19 patients with solid cancer, 12 (100%; 76-100) of 12 healthy controls, and three (60%; 23-88) of five patients with haematological cancers were seropositive, compared with ten (30%; 17-47) of 33, 18 (86%; 65-95) of 21, and four (11%; 4-25) of 36, respectively, who did not receive a boost. The vaccine was well tolerated; no toxicities were reported in 75 (54%) of 140 patients with cancer following the first dose of BNT162b2, and in 22 (71%) of 31 patients with cancer following the second dose. Similarly, no toxicities were reported in 15 (38%) of 40 healthy controls after the first dose and in five (31%) of 16 after the second dose. Injection-site pain within 7 days following the first dose was the most commonly reported local reaction (23 [35%] of 65 patients with cancer; 12 [48%] of 25 healthy controls). No vaccine-related deaths were reported. Interpretation: In patients with cancer, one dose of the BNT162b2 vaccine yields poor efficacy. Immunogenicity increased significantly in patients with solid cancer within 2 weeks of a vaccine boost at day 21 after the first dose. These data support prioritisation of patients with cancer for an early (day 21) second dose of the BNT162b2 vaccine. Funding: King's College London, Cancer Research UK, Wellcome Trust, Rosetrees Trust, and Francis Crick Institute.
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Background Cancer patients presenting with COVID-19 have a high risk of death. In this work, predictive factors for survival in cancer patients with suspected SARS-COV-2 infection were investigated. Methods PRE-COVID-19 is a retrospective study of all 302 cancer patients presenting to this institute with a suspicion of COVID-19 from March 1st to April 25th 2020. Data were collected using a web-based tool within electronic patient record approved by the Institutional Review Board. Patient characteristics symptoms and survival were collected and compared in SARS-COV-2 RT-PCR positive and negative patients. Results 55 of the 302 (18.2%) patients with suspected COVID-19 had detectable SARS-COV-2 with RT-PCR in nasopharyngeal samples. RT-PCR+ patients were older, had more frequently haematological malignancies, respiratory symptoms and suspected COVID-19 pneumonia of CTscan. However, respectively 38% and 20% of SARS-COV-2 RT-PCR negative patients presented similar respiratory symptoms and CT scan images. Thirty of the 302 (9.9%) patients died during the observation period, including 24 (80%) with advanced disease. At the median follow-up of 25 days after first symptoms, the death rate in RT-PCR+ and RT-PCR-patients were 21% and 10% respectively. In both groups, independent risk factors for death were male gender, KPS<60, cancer in relapse, and respiratory symptoms. Detection of SARS-COV-2 on RT-PCR was not associated with an increased death rate (p=0.10). None of the treatment given in the previous month (including cytotoxics, PD1 Ab, anti-CD20, VEGFR2…) correlated with survival. The survival of RT-PCR positive and negative patients with respiratory symptoms and/or COVID-19 type pneumonia on CTscan was similar with a 18.4% and 19.7% death-rate at day-25. Most (22/30, 73%) cancer patients dying during this period were RT-PCR negative. Conclusion The 30-day death rate of cancer patients with or without documented SARS-COV-2 infection is poor, but the majority of deaths occur in RT-PCR negative patients.
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Background: Hepatitis B virus (HBV) reactivation is a serious complication in patients with cancers and HBV infection undergoing immunosuppressant treatment or chemotherapy. However, the safety of anti-programmed cell death (PD) -1 and anti-programmed cell death-ligand 1 (PD-L1) therapy in these patients is unknown because they were excluded from clinical trials of immunotherapy. Methods: This retrospective cohort study involved consecutive hepatitis B surface antigen (HBsAg) -positive cancer patients who were referred to Sun Yat-sen University Cancer Center and received an anti-PD-1/PD-L1 antibody between January 1, 2015 and July 31, 2018. The primary end point was the rate of the occurrence of HBV reactivation. Results: In total, 114 eligible patients were included, among whom 90 (79%) were male, and the median (range) age was 46 (16-76) years. Six patients (5.3%) developed HBV reactivation, occurring at a median of 18 weeks (range, 3-35 weeks) from the commencement of immunotherapy. Among these patients, all of them had undetectable baseline HBV DNA; one had prophylactic antiviral therapy while five did not; four were positive for Hepatitis B e antigen while the other two were negative. At reactivation, the median HBV DNA level was 3.89 × 104 IU/mL (range, 1.80 × 103-6.00 × 107 IU/mL); five had HBV-related hepatitis and one exhibited increasing HBV DNA level without alanine transaminase elevation. No HBV-related fatal events occurred. The lack of antiviral prophylaxis was the only significant risk factor for HBV reactivation (odds ratio, 17.50 [95% CI, 1.95-157.07], P = .004). Conclusions: HBV reactivation occurs in a subset of HBsAg-positive cancer patients undergoing anti-PD-1 or anti-PD-L1 immunotherapy. Regular monitoring of HBV DNA and antiviral prophylaxis are advised to prevent this potentially fatal complication.
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Checkpoint inhibitors are a first-line therapy for advanced melanoma, though their use is limited by diarrhea and colitis. The aim of our study was to determine the risk of these toxicities associated with immunotherapy in advanced melanoma. Electronic databases were searched through June 2017 for prospective studies reporting the risk of diarrhea and colitis in advanced melanoma treated with anti-programmed death-1 (PD-1) or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors. Standardized definitions assessed the grade of diarrhea and colitis. Pooled incidence and weighted relative risk estimates with 95% confidence intervals (CI) were estimated using random effects model. Eighteen studies were included: 6 studies (1537 patients) with PD-1 inhibitors and 15 studies (3116 patients) with CTLA-4 inhibitors. The incidence of all-grade diarrhea was 13.7% (95% CI, 10.1%-17.2%) for anti-PD-1 and 35.4% (95% CI, 30.4%-40.5%) for anti-CTLA-4. The incidence of all-grade colitis was 1.6% (95% CI, 0.7%-2.4%) for anti-PD-1, and 8.8% (95% CI, 6.1%-11.5%) for anti-CTLA-4. When PD-1 inhibitors were compared directly with CTLA-4 inhibitors, the relative risk of all-grade diarrhea was 0.58 (95% CI, 0.43-0.77), and the relative risk of all-grade colitis was 0.16 (95% CI, 0.05-0.51). The rate of therapy discontinuation was numerically higher for anti-CTLA-4 therapy compared with anti-PD-1 therapy. Finally, 2 studies compared combination immunotherapy with anti-CTLA-4 therapy alone. The relative risk of developing all-grade diarrhea and colitis with combination therapy was 1.31 (95% CI, 1.09-1.57) and 1.21 (95% CI, 0.73-1.99), respectively. Diarrhea and colitis are frequent toxicities associated with checkpoint inhibitors, and seem to be most common with CTLA-4 inhibitors.
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Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs’ therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy. Electronic supplementary material The online version of this article (10.1186/s40425-017-0300-z) contains supplementary material, which is available to authorized users.
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Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non-small cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.
Article
Recently in the Liver International, three patients1,2 with AIH during COVID-19 were reported. Τhere is also increasing evidence that vaccination for SARS-CoV-2 may induce autoimmunity3,4. Here, we present a case of histologically confirmed AIH after mRNA vaccination against SARS-CoV-2. A 52-years-old Caucasian woman with no medication history or alcohol abuse and normal liver blood tests during previous periodical checkup, received her 1st dose of the Moderna vaccine on 11th of May 2021.
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The COVID-19 pandemic is still raging across the world and vaccination is expected to lead us out of this pandemic. Although the efficacy of the vaccines is beyond doubt, safety still remains a concern. We report a case of a 65-year-old woman who experienced acute severe autoimmune hepatitis two weeks after receiving the first dose of Moderna-COVID-19 vaccine. Serum immunoglobulin G was elevated and antinuclear antibody was positive (1:100, speckled pattern). Liver histology showed a marked expansion of the portal tracts, severe interface hepatitis and multiple confluent foci of lobular necrosis. She started treatment with prednisolone, with a favorable clinical and analytical evolution. Some recent reports have been suggested that COVID-19 vaccination can lead to the development of autoimmune diseases. It is speculated that the vaccine can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells. Therefore, healthcare providers must remain vigilant during mass COVID-19 vaccination.
Article
To the editor: We have read with interest the recent cases suggesting the possibility of vaccine-induced immune-mediated hepatitis with Pfizer-BioNTech and Moderna mRNA-1273 mRNA vaccines for the SARS-CoV-2 virus. (1), 2), 3), 4), 5), 6), 7)). However, as the cohort of vaccinated individuals against COVID-19 increases, the previously reported cases could not exclude a coincidental development of autoimmune hepatitis, which has an incidence of 3/100 000 population per year (8)). Our case demonstrates conclusive evidence of vaccine-induced immune-mediated hepatitis with a rapid onset of liver injury after the first Moderna dose, which on re-exposure led to acute severe autoimmune hepatitis. https://www.journal-of-hepatology.eu/article/S0168-8278(21)02093-6/fulltext
Article
The vaccines against the severe acute respiratory syndrome coronavirus‐2(SARS‐CoV‐2) were granted a fast‐track authorization due to the catastrophic consequences of Coronavirus disease‐2019 pandemic. Although these vaccines have proven their efficacy, safety has been a concern. Up till now 2 cases of autoimmune hepatitis(AIH) after anti‐SARS‐CoV‐2 vaccination have been reported.
Article
Autoimmune phenomena and clinically apparent autoimmune diseases, including autoimmune hepatitis, are increasingly been reported not only after natural infection with the SARS-CoV-2 virus, but also after vaccination against it. We report the case of a 63-year old man without a history of autoimmunity or SARS-CoV-2 natural infection who experienced acute severe autoimmune-like hepatitis seven days after the first dose of the mRNA-1273 SARS-CoV-2 vaccine. Liver histology showed inflammatory portal infiltrate with interface hepatitis, lobular and centrilobular inflammation with centrilobular necrosis, in absence of fibrosis and steatosis. Serum immunoglobulin G was slightly elevated. Autoimmune liver serology showed an indirect immunofluorescence pattern on triple rodent tissue compatible with anti-mitochondrial antibody (AMA), but, unexpectedly, this pattern was not mirrored by positivity for primary biliary cholangitis (PBC)-specific molecular tests, indicating that this antibody is different from classical AMA. Anti-nuclear antibody (ANA) was also positive with a rim-like indirect immunofluorescence pattern on liver and HEp2 cell substrates, similar to PBC-specific ANA; however, anti-gp210 and a large panel of molecular-based assays for nuclear antigens were negative, suggesting a unique ANA in our patient. He carries the HLA DRB1*11:01 allele, which is protective against PBC. Response to prednisone treatment was satisfactory. The clinical significance of these novel specificities needs to be further evaluated in this emerging condition.
Article
Background & Aims Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aim to use a mouse model to elucidate the immune related molecular mechanisms of hepatitis, one of the common ICI irAEs. Methods Immune phenotyping and molecular profiling were performed on PD1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor, epacadostat, or a 4-1BB agonist antibody. Results ICI combination-induced hepatitis and the 4-1BB agonist mediated hepatitis share similar features yet maintain distinct immune signatures. Both were characterized by an expansion of peri-portal infiltrates and pan-zonal inflammation albeit with different morphologic characteristics. In both cases, infiltrates were predominantly CD4+ and CD8+ T cells with upregulated T cell activation markers ICOS and CD44. Depletion of CD8+ T cells abolished the ICI-mediated hepatitis. Single cell transcriptomics revealed that the hepatitis induced by combination of ICIs is associated with a robust immune activation signature in all subtypes of T cells and Th1 skewing. Expression profiling revealed a central role for IFNγ and liver monocyte-derived macrophages in promoting a pro-inflammatory T cell response to ICI combination and 4-1BB agonism. Conclusion We developed a novel mouse model which offers significant value in yielding deeper mechanistic insight into immune-mediated liver toxicity associated with various immunotherapies. Lay Summary Hepatitis is one of the common immune-related adverse events in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. The mechanisms of ICI-induced hepatitis are not well understood. In this paper, we identify key molecular mechanisms mediating immune intracellular crosstalk between liver T cells and macrophages in response to ICI in a mouse model.
Article
Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T H 1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti–PD-1 and anti–CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T H 1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
Article
Unprecedented loss of life due to the COVID pandemic has necessitated the development of several vaccines in record time. Most of these vaccines have received approval without being extensively whetted for their adverse effect and efficacy profiles. Most adverse effects have been mild, nonetheless, more serious thromboembolic events have also been reported. Autoimmune hepatitis (AIH) can occur in predisposed individuals where an immune mediated reaction against hepatocytes is triggered by environmental factors. Vaccines are a very rare cause of AIH. We report two such cases of AIH triggered by COVID (Covishield) vaccination. While one patient made an uneventful recovery, another succumbed to the liver disease. Ours is the first report of Covishield vaccination related AIH and second ever after any form of COVID vaccination. We hope that our report does not deter COVID vaccination drives. However, we also hope to raise awareness of its potential side effects and the increased role of pharmacovigilance in guiding treatment.
Article
The new vaccines against SARS-CoV-2 are novel in terms of specificity, their wide dissemination across the global population and the inclusion of newly licensed mRNA platforms. We discuss here how the approved vaccines trigger innate immunity to promote durable immunological memory and consider the future implications of protecting populations with these vaccines. This Comment outlines how the recently licensed vaccines for COVID-19 activate innate immune mechanisms to promote immune memory to SARS-CoV-2. The authors also consider future challenges that could limit vaccine efficacy.
Article
Background & aims: Immunotherapy for metastatic cancer may be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-PD-1/PD-L1 and anti-CTLA-4 monoclonal antibodies (mAb). Methods: Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥ 3 hepatitis. Among 16 included patients: 9 received anti-PD-1/PD-L1 while 7 received anti-CTLA-4 mAb, in monotherapy or in combination with anti-PD-1. Liver investigations included viral assays, autoimmune tests and liver biopsy, histological review and immunostaining of liver specimens. Results: Among 16 included patients 9 (56%) were female, median age 63 [33-84] years. Time between therapy initiation and hepatitis was 5 [1-49] weeks, median doses was 2 [1-36]. No patients developed hepatic failure. Histology related to anti-CTLA-4 mAb demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endothelitis. Histology related to anti-PD-1/PD-L1 mAb was characterized by lobular hepatitis. The management of hepatic IRAE was tailored according to the severity both biological and histological of liver injury: 6 patients improved spontaneously, 7 received oral corticosteroids at 0.5-1 mg/kg/day, 2 were maintained on 0.2 mg/kg/day corticosteroids and 1 patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. Conclusions: Acute hepatitis due to immunotherapy for metastatic cancer is rare (3.5%) and in most cases not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful to tailoring patient management, which does not require systematically corticosteroid administration. Lay summary: In patients receiving immunotherapy for metastatic cancer and developing immune-mediated hepatitis, liver biopsy is helpful for diagnosis and evaluation of the severity of liver injury. This study demonstrated the need for a management patient oriented, which could eventually avoid useless systemic corticosteroid treatment.
Article
Background: Dermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known. Methods: We conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented. Results: Rash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab. Conclusion: We found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors.
Vaccinazione COVID-19 per i pazienti oncologicI
  • Associazione Italiana Di Oncologia Medica
  • Aiom Documento
  • Cipomo Comu
Associazione Italiana di Oncologia Medica. Documento AIOM CIPOMO COMU. Vaccinazione COVID-19 per i pazienti oncologicI (2021). www.aiom.it/speciale-covid-19-documento-aiom-cipomo-comu-vaccinazione-covid-19-per-i-pazienti-oncologici/