Severe Acute Hepatitis of Unknown Origin in Children: Exploring the Role of Adenovirus and Potential Cofactors

Adenoviruses are a known cause of self-limiting respiratory, ocular, and gastrointestinal infections in children. However, during the recent outbreak in 2021–2022, the identification of human adenoviruses (HAdV), particularly type F41, as a potential cause of severe acute hepatitis in immunocompetent children has sparked global debate. The unusual severity of liver injury and clustering of cases in immunocompetent children have prompted investigations into whether HAdV is truly hepatotropic or merely an incidental finding. Several hypotheses have been proposed, including adenovirus infection, prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ) infection or adeno-associated virus-2 (AAV2) with a helper virus (HAdV) co-infection. We aim to review the emerging literature on adenovirus and other cofactors as a potential cause of the recent outbreaks of severe acute hepatitis of unknown origin in children (AHUO).