Comparison of three pediatric studies investigating acute hepatitis of unknown etiology

Between 2021 and 2023, approximately 400 pediatric cases of acute hepatitis of unknown etiology (AHUE) were reported in European countries and the United States. In 2023, three pediatric studies revealed that adeno-associated virus serotype 2 (AAV-2) infection was associated with AHUE. This article presents a summary and comparison of the results of metagenomic sequencing, viral whole-genome sequencing, virus-specific real-time polymerase chain reaction (PCR) and histological analysis of the liver, all of which were among the common investigative methods used in the three pediatric studies. All three pediatric studies revealed 80% or greater rates of positivity for AAV-2 in cases of AHUE according to metagenomic sequencing. Moreover, on the basis of PCR results, two studies revealed high AAV-2 positivity rates (96.4% and 81.2%) among cases of AHUE. These findings suggest that AAV-2 is a pathogen in AHUE. Coinfection with AAV-2 and one or more helper viruses (human adenovirus, human herpesvirus 6B, Epstein-Barr virus, <i>etc.</i>), high viral loads of AAV-2 in blood, anti-AAV-2 IgM and human leukocyte antigen typing could be candidate diagnostic criteria for AHUE. AAV-2 infection should be incorporated into clinical guidelines for the management of acute liver failure. Cidofovir can be administered if coinfection with AAV-2 and HAdV is detected.