Unknown Circovirus in Immunosuppressed Patient with Hepatitis, France, 2022.

Hepatitis of undetermined origin can be caused by a wide variety of pathogens, sometimes emerging pathogens. We report the discovery, by means of routine shotgun metagenomics, of a new virus belonging to the family Circoviridae, genus Circovirus, in a patient in France who had acute hepatitis of unknown origin.

Multi-country outbreak of severe acute hepatitis of unknown origin in children, 2022.

AIM: To describe epidemiological characteristics of multi-country outbreak of severe acute hepatitis of unknown origin in children in 2022. METHODS: A descriptive epidemiological study design was used. The review based on the available information concerning this multi-country outbreak aims to summarise the current knowledge about the severe acute hepatitis of unknown origin in children, highlights the suggested working hypotheses, introduces some of the potential explanations for its occurrence and reports on public health measures undertaken to control the disease. RESULTS: Since the first 10 cases of severe acute hepatitis of unknown origin in children in the United Kingdom on 5 April 2022, and up until the 29 August 2022, more than 1000 probable cases have been reported in 35 countries in the world. Up to today, 22 children died in this multi-country outbreak. Despite the numerous theories that have been suggested on the possible underlying causes of the outbreak, an association with hepatitis A-E viruses has been excluded. Adenovirus serotype 41 has been detected in numerous cases, which makes it the most likely underlying cause of the disease. CONCLUSION: Efficient surveillance and comprehension advancements of the epidemiology of this disease are especially important for effective prevention and outbreak response.

AMA-positive hepatitis induced by the SARS-CoV-2 vaccine.

We present the case of a 56-year-old female admitted to our centre for hepatitis. She had recieved the first dose of the BNT162b2 vaccine against SARS-CoV-2 10 days before the admission. Etiologic study was negative. The patient was diagnosed with vaccine-induced hepatitis.

COVID-19 vaccination, dengue hepatitis, and recurrent unilateral anterior uveitis.

A 36-year-old Asian Indian male presented with redness and pain in his right eye of 1 week duration. He was diagnosed to have right acute anterior uveitis and had a history of being admitted at a local hospital for dengue hepatitis a month earlier. He had been on adalimumab 40 mg three weekly once and oral methotrexate 20 mg/week for human leucocyte antigen (HLA) B27 spondyloarthropathy and recurrent anterior uveitis. Our patient had re-activation of his anterior chamber inflammation on three distinct occasions: first, 3 weeks following recovery from coronavirus disease 2019 (COVID-19), the second after the second dose of COVID-19 vaccination, and the third after recovery from dengue fever-associated hepatitis. We propose molecular mimicry and bystander activation as the postulated mechanisms for the re-activation of his anterior uveitis. In conclusion, patients with auto-immune diseases can have recurrent ocular inflammation following COVID-19 or its vaccination or dengue fever as seen in our patient. The anterior uveitis is usually mild and responds to topical steroids. Additional immuno-suppression may not be needed. Mild ocular inflammation following vaccination should not deter individuals from getting COVID-19 vaccination.

Adeno-associated virus 2 infection in children with non-A-E hepatitis.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.

Adeno-associated virus type 2 in US children with acute severe hepatitis.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

Understanding public perceptions in social media responses to posts about acute severe hepatitis of unknown etiology in Indonesia: a qualitative study.

BACKGROUND: Acute Severe Hepatitis of Unknown Etiology (ASHUE) emerged as a new global outbreak in Indonesia early May 2022, coinciding with the COVID-19 pandemic. This study aimed to understand public reactions and responses to the emergence of ASHUE Indonesia and to Government-led disease prevention responses. Understanding how the public perceived government-led preventive messaging about the hepatitis outbreak is crucial to controlling viral spread - particularly given the rapid and unforeseen emergence of ASHUE coincided with COVID-19 and public trust in the Indonesian Government to manage health outbreaks was already tenuous. METHODS: Social media users' responses to information disseminated via Facebook, YouTube, and Twitter were analyzed to understand public perceptions about ASHUE outbreak and their attitudes toward Government-led prevention measures. Data were extracted on a daily basis from 1st May 2022 to 30th May 2022 and analyzed manually. We inductively generated the codes, from which we formed a construct and then grouped to identify themes. RESULTS: A total of 137 response comments collected from 3 social medial platforms were analyzed. Of these, 64 were from Facebook, 57 were from YouTube, and 16 were from Twitter. We identified 5 main themes, including (1) disbelief in the existence of the infection; (2) suspicion about a potential new business after COVID-19; (3) suspicion that COVID-19 vaccine(s) are the cause; (4) religion-related fatalism and (5) trust in government measures. CONCLUSIONS: The findings advance knowledge about public perceptions, reactions and attitudes towards the emergence of ASHUE and the efficacy of disease countermeasures. The knowledge from this study will provide an understanding of why disease prevention measures might not be followed. It can be used to develop public awareness programs in Indonesia about both the ASHUE and its possible consequences and the available healthcare support.

Etiology of Severe Acute Hepatitis in a Pediatric Transplant Center in Japan.

The proportion of pediatric cases with severe acute hepatitis of unknown etiology in the coronavirus disease 2019 era was higher than that in the pre-coronavirus disease 2019 era in Japan's largest pediatric transplant center. Further research and monitoring are essential.

Severe Hepatitis-associated Aplastic Anemia Following COVID-19 mRNA Vaccination.

We herein report a case of hepatitis-associated aplastic anemia (HAAA) that occurred after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. In this patient, progressive pancytopenia observed two months after acute hepatitis following the second dose of the SARS-CoV-2 vaccine indicated the development of HAAA. Although some reports have suggested that SARS-CoV-2 vaccination may be involved in the development of autoimmune diseases, no cases of HAAA developing after SARS-CoV-2 vaccination have been reported. SARS-CoV-2 vaccination in children has only started relatively recently, so the range of side effects in children has not yet been thoroughly described. Therefore, we need to strengthen surveillance for symptoms of children who are vaccinated.

Acute severe non-A-E-hepatitis of unknown origin in children - A 30-year retrospective observational study from north-west Germany.

BACKGROUND & AIMS: The etiology of the current acute severe non-A-E hepatitis epidemic in children remains unclear. We aimed to describe the occurrence and outcomes of acute severe hepatitis in pediatric patients in North-West Germany over a period of more than 30 years and in the context of the current epidemic. METHODS: We analyzed all cases of acute severe hepatitis in childhood, as defined by the World Health Organization, at Hannover Medical School from 1990 and at the University Hospital of Essen from 2009 to 16 May 2022. We separated cases into a historic cohort (1990-2018) and a COVID-19 era cohort (2019-2022). RESULTS: After application of exclusion criteria, 107 patients with acute severe hepatitis were identified (2.32 cases/center/year). Annual incidence per center rose significantly from 2.2 (historic cohort until 2018) to 4.25/center/year (from 2019, p = 0.002). Of all cases, 75.7% presented with jaundice, while 53.3% had clinical signs of infection. Two cases of adenovirus were proven (2004/2016), other pathogens detected were HHV-6 (4), CMV, HSV, EBV(3). Sixty-nine patients (64.5%) met the criteria of pediatric acute liver failure, with 44 requiring liver transplantation. In the current cohort, patients with infection, gastrointestinal symptoms and higher alanine aminotransferase had a better chance of transplant-free survival, whereas hepatic encephalopathy, higher international normalized ratio and bilirubin predicted a poor outcome. Twenty-five patients developed hepatitis-associated aplastic anemia and 19 patients (17.8%) died. CONCLUSIONS: Acute non-A-E-hepatitis in children is a rare but severe entity, often leading to acute liver failure. Clinical presentation in our current cohort resembles 2022 NAEH cases, with improved outcomes compared to historic controls. The rising incidence of NAEH in our centers since 2019, in the absence of adenoviral infection, indicates other potential triggers of similar NAEH cases. IMPACT AND IMPLICATIONS: As the current epidemic of severe acute non-A-E-hepatitis cases in children highlights our limited understanding in the field, we aim to describe current cases, characterizing the presentation over time, and defining similarities and discrepancies before and during the COVID-19 pandemic. Our data show a rising incidence of non-A-E-hepatitis cases since the beginning of the COVID-19 pandemic. These cases were not associated with adenoviral infections, suggesting that the recently described accumulation of adenovirus infections in relationship to hepatitis is a new trigger for a known phenomenon, rather than a new disease entity. Therefore, the role of protective isolation and subsequent lack of contact with trivial infections in children during the pandemic should be the subject of further examinations. We expect our data to contribute to a better understanding of severe acute hepatitis in childhood, increased vigilance for this potentially lethal disease beyond the current epidemic, and ultimately improved clinical diagnosis and care.

Acute severe hepatitis as a presenting symptom in clinically stable patients admitted with SARS-CoV-2 Omicron infection.

BACKGROUND: Suggested mechanisms for SARS-CoV-2 direct liver infection have been proposed by others to involve both cholangiocytes and hepatocytes. Early clinical studies have highlighted abnormal liver biochemistry with COVID-19 infection as often not being severe, with elevated liver enzymes <5X the upper limit of normal. METHODS: Liver enzymes were evaluated and compared in patients admitted with a diagnosis of COVID-19 in a deidentified Internal Medicine-Medical Teaching Unit/hospitalist admission laboratory database. Comparisons in the incidence of severe liver injury (alanine aminotransferase >10 times upper limit of normal) were made for patients with pre-Omicron SARS-CoV-2 (November 30, 2019, to December 15, 2021) and Omicron SARS-CoV-2 (December 15, 2021, to April 15, 2022). Comprehensive hospital health records were also reviewed for the 2 patient cases discussed. One patient had a liver biopsy that was evaluated with H&E and immunohistochemistry staining using an antibody against COVID-19 spike protein. RESULTS: The evaluation of a deidentified admissions laboratory database found the incidence of severe liver injury was 0.42% with Omicron versus 0.30% with pre-Omicron variants of COVID-19. In both patient cases discussed, abnormal liver biochemistry and a negative comprehensive workup strongly suggest COVID-19 as the cause of severe liver injury. In the one patient with liver biopsy, immunohistochemistry staining suggests SARS-CoV-2 presence in the portal and lobular spaces in association with immune cell infiltration. CONCLUSIONS: The Omicron variant of SARS-CoV-2 should be considered in the differential diagnosis of severe acute liver injury. Our observation suggests that this new variant, either through direct liver infection and/or mediating immune dysfunction, can result in severe liver injury.

Pediatric Hepatitis and Respiratory Viruses: A Spatiotemporal Ecologic Analysis.

INTRODUCTION: Beginning in early 2022, clusters of severe pediatric hepatitis were reported in Europe and the United States. To date, no cause has been identified although human adenovirus 41 has been proposed in a proportion of cases. We examined population data >11 years for hepatitis clusters in Victoria, Australia, and whether any were spatiotemporally associated with community transmission of common respiratory viruses. METHODS: We used SaTScan to analyze for clusters of pediatric hepatitis and respiratory adenoviruses in Victoria. Negative binomial regression analysis was performed to determine any associations between hepatitis and respiratory viruses across Victoria between July 1, 2011, and June 30, 2022. RESULTS: A number of positive associations were observed in Victoria between pediatric hepatitis clusters and respiratory viruses in our spatiotemporal analysis. A positive association was not found with respiratory adenoviruses or SARS-CoV-2. Increased hepatitis clusters were observed in 2021 and 2022 as noted internationally. CONCLUSION: The current hepatitis outbreak is novel and, although respiratory viruses are broadly associated with hepatitis, SARS-CoV-2 and respiratory adenoviruses are unlikely to be related.

Severe acute hepatitis of unknown origin.

At the beginning of 2022, in the United Kingdom, and later in several European countries, a group of pediatric patients who developed acute hepatitis of so far unknown origin was reported. Clinical data include nausea, vomiting, jaundice, and liver failure; some patients require liver transplantation. The affected population is younger than 10 years of age. The probable etiological agent is adenovirus genotype F41, and toxic factors have been ruled out, as well as a relationship with COVID-19. There are several theories to explain this phenomenon, which are being investigated.

A inicios de 2022, en Reino Unido, y posteriormente en varios países europeos, se informó sobre un grupo de pacientes pediátricos que desarrollaron hepatitis aguda de origen desconocido hasta ahora. Los datos clínicos consisten en náusea, vómito, ictericia y falla hepática; algunos pacientes necesitan trasplante hepático. La población afectada es menor a los 10 años. El agente etiológico probable es el adenovirus genotipo F41 y se han descartado factores tóxicos, así como la relación con COVID-19. Existen varias teorías para explicar este fenómeno, las cuales se están investigando.