Severe acute hepatitis of unknown origin in children: Is it still a mystery? What role does adenovirus play?

On March 31, 2022, severe acute hepatitis of unknown origin was first reported from the Royal Glasgow Children's Hospital in Scotland. According to the criteria by WHO-ECDC, a probable case of unknown acute hepatitis in children is defined as a subject under 16 years of age, who tested negative for viral hepatitis and transaminases >500 U/L, starting from the 1st of October 2021. WHO invites Member States to participate in the global effort to collect anonymized clinical data on probable cases of severe acute hepatitis of unknown aetiology. As of May 26, 2021, 650 cases were already registered on the platform worldwide, of whom at least 38 cases have required liver transplants. Several hypotheses such as previous SARS-CoV-2 infection or coinfection or infection with another virus were examined and a strong association was found between adenovirus (41F) and acute hepatitis of unknown aetiology cases. This review article summarizes the global epidemiological evidences on acute hepatitis of unknown origin in children, analysing their incidence and characteristics.