Severe acute hepatitis in children: true outbreak or heightened vigilance?

The COVID-19 pandemic, with its high number of deaths, has inevitably raised the level of attention towards all the diffusive infectious diseases that are potentially capable of damaging public health. Therefore, attention and concern have been given to a cluster of acute hepatitis, which developed in young children in 2022 and occurred initially in Scotland and later in other countries, including the USA. Although there was no defined cause and not all cases had received the same diagnostic investigations to exclude all possible causes of acute hepatitis, an aetiopathogenetic homogeneity among the reported cases was generally accepted. Various aetiological hypotheses have been formulated and the greatest attention has been focused on the role of adenovirus (HAdV) F41 and adeno-associated virus 2 (AAV2). 1 Grand RJ Pathogenicity and virulence of human adenovirus F41: possible links to severe hepatitis in children. Virulence. 2023; 142242544 Crossref Scopus (0) Google Scholar Firstly, two studies from the UK and USA found an association between HAdV and the acute hepatitis cases. 2 Kelgeri C Couper M Gupte GL et al. clinical spectrum of children with acute hepatitis of unknown cause. N Engl J Med. 2022; 387: 611-619 Crossref PubMed Scopus (43) Google Scholar , 3 Gutierrez Sanchez LH Shiau H Baker JM et al. A case series of children with acute hepatitis and human adenovirus infection. N Engl J Med. 2022; 387: 620-630 Crossref PubMed Scopus (8) Google Scholar Later, UK case-control investigations detected AAV2 infection with high concentrations of AAV2 DNA in blood and liver samples from affected children. It was hypothesised that AAV2 replication was favoured by the concomitance of other viruses such as HAdV and human herpes virus-6B. Furthermore, an association between AAV2 infection and host human leucocyte antigen (HLA) type was identified, supporting the role of an individual susceptibility promoting a severe immune-mediated response to the viral trigger. 4 Ho A Orton R Tayler R et al. Adeno-associated virus 2 infection in children with non-A-E hepatitis. Nature. 2023; 617: 555-563 Crossref PubMed Scopus (15) Google Scholar , 5 Morfopoulou S Buddle S Torres Montaguth OE et al. Genomic investigations of unexplained acute hepatitis in children. Nature. 2023; 617: 564-573 Crossref PubMed Scopus (17) Google Scholar The AAV2 hypothesis was also supported by a US study that identified a distinct strain of AAV2 and coinfection with at least one helper virus in the blood of affected chidren. 6 Servellita V Sotomayor Gonzalez A Lamson DM et al. Adeno-associated virus type 2 in US children with acute severe hepatitis. Nature. 2023; 617: 574-580 Crossref PubMed Scopus (15) Google Scholar Additionally, other factors were considered, such as SARS-CoV-2 infection and sudden exposure of children to multiple viruses after lockdown, resulting in increased susceptibility to ordinarily harmless viruses. 7 Tacke F Severe hepatitis outbreak in children linked to AAV2 virus. Nature. 2023; 617: 471-472 Crossref PubMed Scopus (4) Google Scholar Paediatric acute hepatitis of unknown aetiology: a national investigation and adenoviraemia case-control study in the UKWe observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. Full-Text PDF Open AccessPaediatric acute hepatitis of unknown aetiology: a national surveillance investigation in the USA during 2021 and 2022Adenovirus, alone or in combination with other factors, might play a potential role in acute hepatitis among immunocompetent children identified in this investigation, but the pathophysiologic mechanism of liver injury is unclear. To inform both prevention and intervention measures, more research is warranted to determine if and how adenovirus might contribute to hepatitis risk and the potential roles of other pathogens and host factors. Full-Text PDF