Hepatitis of Unknown Origin and Etiology (Acute Non HepA-E Hepatitis) among Children in 2021/2022: Review of the Current Findings

Several clusters and individual cases of acute hepatitis have been reported in the US, Europe and recently in Asia and Central America since October 2021. A laboratory investigation of the common viral hepatitis agents (HAV, HBV, HCV, HDV and HEV) yielded negative results prompting the use of the term "acute non HepA-E hepatitis" to describe this condition. The cases were characterized by the manifestations of acute hepatitis (abdominal pain, vomiting, diarrhea, jaundice and very high levels of liver enzymes) affecting children with a median age of 3-4 years. The exact underlying etiology has not been revealed yet; however, a leading hypothesis is that an infectious agent is the culprit, underlying cause or a risk factor for acute non HepA-E hepatitis occurrence. So far, laboratory testing has shown the presence of the group F human adenovirus serotype 41 (HAdV-F41) in about three-fourths of the investigated cases. As of 13 May 2022, more than 450 cases were reported worldwide, the majority of which were in the UK (n = 176), the US (n = 109), 13 European countries (at least 103 cases) and in Argentina, Brazil, Canada, Costa Rica, Indonesia, Israel, Japan, Palestine, Panama, Singapore and South Korea. Vigilant surveillance and epidemiologic investigations to identify further cases are warranted to delineate the features of this emergent public health issue. The possible role of environmental and toxic agents including foodborne toxins should also be considered. Specific guidelines for identification of further cases are necessary, particularly in low-income settings where testing for adenoviruses is not considered routinely. A genetic analysis of HAdV-F41 isolates is recommended to assess the potential changes in the virus genome with subsequent possible altered virus behavior. Immunopathogenesis is another possibility that should be evaluated considering the lack of viral structures in liver biopsies of the affected children in the US.