AUTHOR=Bousfiha Mohamed , Ben Sabbahia Dalal , Jouanguy Emmanuelle , Casanova Jean-Laurent , El Bakkouri Jalila , Bousfiha Ahmed Aziz , Amenzoui Naima 
  
TITLE=Genetic and autoimmune predispositions to fulminant viral hepatitis in children
  
JOURNAL=Frontiers in Immunology
  
VOLUME=Volume 17 - 2026
  
YEAR=2026
  
URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1858895
  
DOI=10.3389/fimmu.2026.1858895
  
ISSN=1664-3224
  
ABSTRACT=Fulminant viral hepatitis (FVH) in children is a rare but often fatal form of acute liver failure occurring in the absence of preexisting liver disease. Its exceptional incidence during otherwise common viral infections, including hepatitis A virus (HAV), hepatitis B virus (HBV), and herpes simplex virus (HSV), supports a decisive role for host susceptibility. Recent advances in human immunogenetics delineate two major, mechanistically distinct pathways to pediatric FVH. The first reflects failure of immune regulation, culminating in excessive IFN-γ–driven inflammation and immune-mediated hepatocellular necrosis. Autosomal recessive IL-18BP and IL-10RB deficiencies exemplify this mechanism, in which disruption of key regulatory checkpoints permits uncontrolled activation of cytotoxic lymphocytes and macrophage-dependent immunopathology, particularly in the context of HAV infection. The second pathway involves impaired intrinsic antiviral defense, most prominently through neutralizing autoantibodies against type I interferons, which phenocopy genetic defects of IFN-I signaling and are strongly associated with HSV-triggered FVH; in this setting, inadequate early antiviral control enables unchecked hepatic replication with extensive cytopathic damage. Finally, syndromic hyperinflammatory disorders, including familial hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease, broaden the spectrum of immune predisposition in which fulminant hepatitis may arise. Together, these discoveries redefine pediatric FVH as an immunopathological syndrome and provide a framework for targeted genetic and serologic diagnosis and for mechanism-based interventions aimed at improving survival.