Introduction: Non-A–E hepatitis (NAEH) is a rare but increasingly recognized cause of acute liver injury in children. While the etiology remains unclear, clinical presentation can be severe, with some cases progressing to acute liver failure (PALF) or hepatitis-associated aplastic anemia (HAAA). Following the global outbreak of unexplained pediatric hepatitis in 2022, questions have emerged about post-COVID immune dysregulation. This study presents a 15-year retrospective analysis of pediatric NAEH, focusing on liver transplantation and transplant-free survival before and after the COVID-19 pandemic.
Methods: Pediatric patients (3 months–18 years) diagnosed with acute NAEH between 2009 and 2024 at a tertiary liver transplant center were included. Inclusion required ALT or AST >500 U/L and exclusion of known hepatitis causes. Patients were stratified into pre-COVID (2009–2018) and post-COVID (2019–2024) cohorts. We analyzed disease severity, transplant listing (including high urgency status), transplant-free survival, histopathologic findings, and infectious triggers.
Results: Forty-nine patients were identified, with a rise in annual cases post-COVID (5.8 vs. 2.0/year). Despite comparable baseline characteristics, liver transplantation was significantly less frequent post-pandemic (6.8% vs. 40%, p = 0.0137), indicating improved transplant-free survival. Ten patients (20.4%) underwent liver transplantation, including seven listed as high urgency (median wait time: 2 days). Transplant was associated with hepatic encephalopathy, elevated INR, and lower ALT levels at admission, while ALT >3000 U/L predicted spontaneous recovery (p = 0.044). Histopathology (n=35) showed severe hepatocyte necrosis, mixed inflammatory infiltrates, and early fibrosis. Viral screening revealed potential triggers in 53% (e.g., HHV-6, EBV, influenza B), but no confirmed adenovirus despite near-universal testing. Fourteen patients (28.6%) developed HAAA, typically with delayed cytopenia (~4 weeks post-hepatitis). While hepatic function generally recovered without transplantation in these patients, six required hematopoietic stem cell transplantation.
Conclusion: This 15-year review reveals an increase in pediatric NAEH cases in the post-COVID era, alongside improved transplant-free survival and reduced high-urgency liver transplantation. A significant subset developed HAAA, often following severe hepatitis without PALF, yet requiring hematologic intervention. Histological and viral findings support immune-mediated injury. Early risk stratification remains key to guiding both liver and hematologic transplant decisions.