According to the World Health Organization, the criteria for a probable diagnosis of severe acute hepatitis of unknown etiology are: (1) onset after October 1, 2021; ( 2) aspartate aminotransferase (AST) level or alanine aminotransferase (ALT) level ≥ 500 IU/L; ( 3) age at onset ≤ 16 years; ( 4) exclusion of hepatitis A–E and absence of clear etiology. 1 Some affected children have developed acute liver failure (ALF), which requires more intensive care and liver transplants; some of these children have died. The detection of HHV-6B DNA in plasma and liver tissue provided reasonable evidence to rule out chromosomal integration of HHV-6B. 9 Herpes simplex virus The clinical manifestations of herpes simplex virus (HSV) infection are mostly mild and self-limiting. Similar to HCMV, DNA from EBV and HHV-6 is frequently detected in immunocompetent children with acute liver dysfunction. ...polymerase chain reaction and serological assessments are both necessary for the accurate diagnosis and treatment of children with acute hepatic insufficiency caused by primary herpesvirus infection. Symptoms of hepatitis caused by HEV infection are mild, with rare instances of severe jaundice or elevated levels of ALT, AST, and bilirubin; affected patients generally have a good prognosis. 15 The natural course of the disease may be prolonged in immunocompromised hosts. ...there is a need to carefully monitor the indicators of HEV infection, considering its involvement in neonatal ALF or hepatitis, to enable a more rational diagnosis and management.