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Severe de novo liver injury after Moderna vaccination – not always autoimmune hepatitis
... An important finding of this study was that three months after treatment, only 58% had achieved a complete biochemical response to immunosuppressive treatment [91]. Finally, a case report by Nyein et al. was excluded, as it could not be characterized as an immune-mediated liver injury [92]. Interestingly, this was the first case with the detection of anti-SARS-CoV-2 specific antibodies scattered throughout liver parenchyma [92]. ...
... Finally, a case report by Nyein et al. was excluded, as it could not be characterized as an immune-mediated liver injury [92]. Interestingly, this was the first case with the detection of anti-SARS-CoV-2 specific antibodies scattered throughout liver parenchyma [92]. ...
... There are several reports resembling IM-DILI in patients developing clinical hepatitis following SARS-CoV-2 vaccination, without any autoimmune feature (such as the presence of autoantibodies, an IgG increase, a compatible liver histology, or a good response to immunosuppressants) or with a varying expression of these features [54,62,79,89,90,92,103]. These cases, though severe at times, are usually self-resolving without further management needed. ...
Background:
There is an increasing number of liver injury cases resembling autoimmune hepatitis (AIH) following SARS-CoV-2 vaccination; however, an association has not yet been established.
Methods/materials:
A literature review was performed to identify articles regarding the association of AIH with vaccination, emphasizing on SARS-CoV-2 vaccines, and the proposed mechanisms. We then performed a literature search for AIH-like cases following SARS-CoV-2 vaccination, and we evaluated the included cases for AIH diagnosis using simplified diagnostic criteria (SDC), and for vaccination causality using the Naranjo score for adverse drug reactions.
Results:
We identified 51 AIH-like cases following SARS-CoV-2 vaccination. Forty cases (80%) were characterized as "probable", "at least probable", or "definite" for AIH diagnosis according to SDC. Forty cases (78.4%) were characterized as "probable", four (7.8%) as "possible", and three (5.8%) as "definite" for vaccine-related AIH according to the Naranjo score.
Conclusion:
SARS-CoV-2 vaccine-related AIH carries several phenotypes and, although most cases resolve, immunosuppressive therapy seems to be necessary. Early diagnosis is mandatory and should be considered in any patient with acute or chronic hepatitis after SARS-CoV-2 vaccination, especially in those with pre-existing liver disease.
... Autoimmune hepatitis (AIH) was the first most-common liver disease reported following COVID-19 vaccination [eighty-three new onset cases [6-8, 37, 41, 68, 84, 85, 87, 97, 99, 101-108, 110, 112, 115, 117-120, 123, 124, 126, 127] and four previously known cases [43,80,86,104]; and in fifty-one cases event if new-onset or relapsed was not reported [42]] (see Table 1). Most common clinical presentations in these AIH cases were fatigue (n = 75) [99, 102-104, 112, 118, 119, 124, 126, 127], jaundice (n = 68), [6-8, 37, 42, 68, 84, 85, 97, 99, 102, 104-108, 110, 112, 115, 117, 118, 123, 126, 127], nausea (n = 60) [68,108,112,123,126,127], abdominal pain (n = 25) [7,37,68,105,126], pruritus (n = 10) [6,37,99,101,105,110,117,127], itching (n = 10) [126], dark urine (n = 10) [6,7,68,84,103,104,106,108,110,123], hepatomegaly (n = 6) [6,7,85,102,103,123], fever (n = 5) [84,104,117,123], malaise (n = 4) [84,85,97,112], anorexia (n = 4) [8,102,104,112], and yellow eyes (n = 4) [8,103,112,118]. Four of the AIH cases were asymptomatic [43,80,86,87]. ...
... Autoimmune hepatitis (AIH) was the first most-common liver disease reported following COVID-19 vaccination [eighty-three new onset cases [6-8, 37, 41, 68, 84, 85, 87, 97, 99, 101-108, 110, 112, 115, 117-120, 123, 124, 126, 127] and four previously known cases [43,80,86,104]; and in fifty-one cases event if new-onset or relapsed was not reported [42]] (see Table 1). Most common clinical presentations in these AIH cases were fatigue (n = 75) [99, 102-104, 112, 118, 119, 124, 126, 127], jaundice (n = 68), [6-8, 37, 42, 68, 84, 85, 97, 99, 102, 104-108, 110, 112, 115, 117, 118, 123, 126, 127], nausea (n = 60) [68,108,112,123,126,127], abdominal pain (n = 25) [7,37,68,105,126], pruritus (n = 10) [6,37,99,101,105,110,117,127], itching (n = 10) [126], dark urine (n = 10) [6,7,68,84,103,104,106,108,110,123], hepatomegaly (n = 6) [6,7,85,102,103,123], fever (n = 5) [84,104,117,123], malaise (n = 4) [84,85,97,112], anorexia (n = 4) [8,102,104,112], and yellow eyes (n = 4) [8,103,112,118]. Four of the AIH cases were asymptomatic [43,80,86,87]. ...
... The median (IQR) time between the COVID-19 vaccination and time of presentation was 14 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) days. Seventy-seven, twenty-nine, and twenty-nine of these one hundred-thirty eight cases were reported following Pfizer-BioNTech (eight after the first dose, eight after the second dose and three after the third dose) [6,41,43,68,84,87,99,105,106,112,115,119,120,123,124,127], Moderna (nine after the first dose and three after the second dose) [7,8,80,85,97,99,102,103,107,108,117,126], and Oxford Uni-AstraZeneca (three after the first dose, two after the second dose and one after the third dose) [37,86,99,101,115,126] vaccination; respectively. Ten AIH patients had a history of thyroid gland disorders [Hashimoto's thyroiditis (n = 6) [42,103,106,112] and hypothyroidism (n = 4) [68,86,104,127]] and seven patients had no medical history (n = 7, 5.1%) [85,97,110,115,117,119,123], however, some of the patients had a past medical history of hypertension (n = 17, 12.3%) [6,101,112,118,126] [102,104,126], hyperlipidaemia (n = 6, 4.3%) [8,84,105,106,115,118], and rheumatoid arthritis (n = 2, 1.4%) [42]. ...
Background: Liver diseases post-COVID-19 vaccination is extremely rare but can occur. A growing body of evidence has indicated that portal vein thrombosis, autoimmune hepatitis, raised liver enzymes and liver injuries, etc., may be potential consequence of COVID-19 vaccines.
Objectives: To describe the results of a systematic review for new-onset and relapsed liver disease following COVID-19 vaccination.
Methods: For this systematic review, we searched Proquest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses PRISMA guideline for studies on the incidence of new onset or relapsed liver diseases post-COVID-19 vaccination, published from December 1, 2020 to July 31, 2022, with English language restriction.
Results: Two hundred seventy-five cases from one hundred and eighteen articles were included in the qualitative synthesis of this systematic review. Autoimmune hepatitis (138 cases) was the most frequent pathology observed post-COVID-19 vaccination, followed by portal vein thrombosis (52 cases), raised liver enzymes (26 cases) and liver injury (21 cases). Other cases include splanchnic vein thrombosis, acute cellular rejection of the liver, jaundice, hepatomegaly, acute hepatic failure and hepatic porphyria. Mortality was reported in any of the included cases for acute hepatic failure (n=4, 50%), portal vein thrombosis (n=25, 48.1%), splanchnic vein thrombosis (n=6, 42.8%), jaundice (n=1, 12.5%), raised liver enzymes (n=2, 7.7%), and autoimmune hepatitis (n=3, 2.2%). Most patients were easily treated without any serious complications, recovered and did not require long-term hepatic therapy.
Conclusion: Reported evidence of liver diseases post-COIVD-19 vaccination should not discourage vaccination against this worldwide pandemic. The number of reported cases is relatively very small in relation to the hundreds of millions of vaccinations that have occurred and the protective benefits offered by COVID-19 vaccination far outweigh the risks.
... A few cases of liver injury after SARS-CoV-2 infection [30][31][32][33][34] and COVID-19 vaccination [35,36], not presenting with an AIH pattern and resembling a drug-induced liver injury (DILI), have also been reported in the literature. DILI is a rare but sometimes severe adverse drug reaction that manifests with th eelevation of liver enzymes, with or without non-specific symptoms [37]. ...
(1) Background: Despite the advantages of COVID-19 vaccination, rare cases of acute hepatitis developing after the administration of the COVID-19 vaccine or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. The aim of the study is to describe a case series of patients who experienced the onset of acute hepatitis, with or without autoimmune features, following SARS-CoV-2 vaccination or infection and to hypothesize a genetic susceptibility in the pathogenesis. (2) Methods: A group of patients with acute onset hepatitis following SARS-CoV-2 vaccination or infection were evaluated in our hepatology outpatient clinic, where they underwent biochemical and autoimmune tests. Hepatitis A (HAV), B (HBV), and C virus (HCV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and human immunodeficiency virus (HIV) infections were excluded. Patients with a diagnosis of autoimmune hepatitis (AIH) or drug-induced liver injury (DILI) underwent HLA typing and histological testing. (3) Results: Five patients experienced new-onset AIH after COVID-19 vaccination, one of which developed mild symptoms after vaccination that strongly worsened during subsequent SARS-CoV-2 infection. One patient had AIH relapse after COVID-19 vaccination while on maintenance immunosuppressive treatment. All of them had HLA DRB1 alleles known to confer susceptibility to AIH (HLA DRB1*03,*07,*13,*14), and in three of them, HLA DRB1*11 was also detected. Two patients developed acute hepatitis without autoimmune hallmarks which resolved spontaneously, both positive for HLA DRB1*11. (4) Conclusions: An association between AIH and COVID-19 vaccine or infection can be hypothesized in individuals with a genetic predisposition. In patients without autoimmune features and spontaneous improvement of hypertransaminasemia, the diagnosis of drug-induced liver injury (DILI) is probable. Further studies are needed to determine the presence of an actual association and identify a possible role of HLA DRB1*11 in the pathogenesis of acute liver injury after SARS-CoV2 vaccination or infection.
... Other proposed mechanisms are bystander activation and epitope spreading [6] as well as molecular mimicry [7]. Interestingly, some reports suggest the possibility of SARS-CoV-2 Spike protein expression within hepatocytes after vaccination [9] and the presence of an immune infiltrate characterized by activated cytotoxic CD8 T-cells with SARS-CoV-2 Spike-protein specificity [10]. ...
Eindverslag van het onderzoek naar een mogelijke relatie tussen Covid-19 vaccinaties en oversterfte in Nederland 2021 - 2023
Eindverslag van het onderzoek naar een mogelijke relatie tussen Covid-19 vaccinaties en oversterfte in Nederland 2021 - 2023
Here, we report an 86-year-old Japanese woman presenting with confluent maculopapular erythema, which developed following the second dose of COVID-19 Messenger RNA (mRNA) vaccine (BNT162b2). Her skin lesions spread over time and persisted for more than 3 months. Surprisingly, immunohistochemical staining of the lesion 100 days after the disease onset revealed the COVID-19 spike protein expressed by vascular endothelial cells and eccrine glands in the deep dermis. As she had no episode of COVID-19 infection, it is highly likely that the spike protein was derived from the mRNA vaccine and it might be the cause of the development and persistence of her skin lesions. Her symptoms were prolonged and intractable until oral prednisolone was given.
Several vaccines have been developed for coronavirus disease 2019 (COVID-19) and are used worldwide. Here we report a case of severe acute hepatitis induced by COVID-19 vaccination. A 54-year-old woman received two doses of the Pfizer-BioNTech COVID-19 mRNA vaccine and an additional dose of the Moderna COVID-19 mRNA vaccine. Seven days after the third dose, she noticed fatigue, appetite loss and dark urine. Laboratory tests were consistent with severe liver injury and jaundice. Anti-smooth muscle antibody and HLA-DR4 were positive; thus, we suspected that she had autoimmune hepatitis (AIH). Intravenous methylprednisolone followed by oral prednisolone were administered. Because remission was not achieved, we performed percutaneous liver biopsy. Histologically, pan-lobular inflammation with moderate infiltration of lymphocytes and macrophages, interface hepatitis, and rosette formation were present. We regarded these findings as confirmation of the diagnosis of AIH. As she had not responded to corticosteroids, we added azathioprine. Liver biochemistry tests gradually improved, and prednisolone could be tapered without relapse of AIH. Dozens of cases of AIH after COVID-19 vaccination have been reported. Corticosteroids were effective in most cases, but some patients have died from liver failure after vaccination. This case illustrates the efficacy of azathioprine for steroid-refractory AIH induced by COVID-19 vaccination.
We here report the first case of anti-proteinase 3 (PR3) positive ANCA-associated vasculitis following SARS-CoV-2 Pfizer-BioNTech vaccine presenting with prominent liver involvement and alveolar hemorrhage. Two weeks after vaccination, a 49-year-old man developed inflammatory arthralgias and hypertransaminasemia. Two months later, fever and hemoptysis appeared; the patient tested positive for anti-PR3 autoantibodies. High dose steroids and rituximab were started, and complete remission was achieved. Systemic autoimmune diseases, including ANCA-associated vasculitis, should always be considered in the differential diagnosis of hypertransaminasemia, especially when the clinical context is suspicious.
Background
COVID-19 is diagnosed via detection of SARS-CoV-2 RNA using real time reverse-transcriptase polymerase chain reaction (rtRT-PCR). Performance of many SARS-CoV-2 rtRT-PCR assays is not entirely known due to the lack of a gold standard. We sought to evaluate the false negative rate (FNR) and sensitivity of our laboratory-developed SARS-CoV-2 rtRT-PCR targeting the envelope (E) and RNA-dependent RNA-polymerase (RdRp) genes.
Methods
SARS-CoV-2 rtRT-PCR results at the Public Health Laboratory (Alberta, Canada) from January 21 to April 18, 2020 were reviewed to identify patients with an initial negative rtRT-PCR followed by a positive result on repeat testing within 14 days (defined as discordant results). Negative samples from these discordant specimens were re-tested using three alternate rtRT-PCR assays (targeting the E gene and N1/N2 regions of the nucleocapsid genes) to assess for false negative (FN) results.
Results
During the time period specified, 95,919 patients (100,001 samples) were tested for SARS-CoV-2. Of these, 49 patients were found to have discordant results including 49 positive and 52 negative swabs. Repeat testing of 52 negative swabs found five FNs (from five separate patients). Assuming 100% specificity of the diagnostic assay, the FNR and sensitivity in this group of patients with discordant testing was 9.3% (95% CI 1.5–17.0%) and 90.7% (95% CI 82.6–98.9%) respectively.
Conclusions
Studies to understand the FNR of routinely used assays are important to confirm adequate clinical performance. In this study, most FN results were due to low amounts of SARS-CoV-2 virus concentrations in patients with multiple specimens collected during different stages of infection. Post-test clinical evaluation of each patient is advised to ensure that rtRT-PCR results are not the only factor in excluding COVID-19.
Background
Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.
Methods
This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2.
Results
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The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.
Conclusions
The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
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
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.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins were measured in longitudinal plasma samples collected from 13 participants who received two doses of mRNA-1273 vaccine. Eleven of 13 participants showed detectable levels of SARS-CoV-2 protein as early as day 1 after first vaccine injection. Clearance of detectable SARS-CoV-2 protein correlated with production of immunoglobulin G (IgG) and immunoglobulin A (IgA). © 2021 The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]