Characterization of a Hepatitis Outbreak in Children, 2021 to 2022

Abstract

ImportanceAfter a cluster of pediatric cases of hepatitis of unknown etiology were identified in Scotland in March 2022, the World Health Organization published an outbreak alert, and more than 1010 probable cases were reported. Some cases progressed to acute liver failure and required liver transplant. Although many patients had positive results for adenovirus on polymerase chain reaction testing from whole blood samples and/or reported recent COVID-19 infection (with or without seropositivity), the precise pathogenesis remains unclear despite the high potential morbidity of this condition.ObjectiveTo summarize the currently available evidence regarding novel pediatric hepatitis of unknown etiology (or novel hepatitis), encompassing case numbers, testing, management, and outcomes.Evidence ReviewA rapid review of the literature from April 1, 2021, to August 30, 2022, aimed to identify all available published case series and case-control studies of novel hepatitis. The search included PubMed and references and citations of short-listed studies.FindingsA total of 22 available case series and case-control studies describing 1643 cases were identified, with 120 children (7.3%) receiving liver transplants and 24 deaths (1.5%). Outcome reporting and testing for adenovirus and SARS-CoV-2 was incomplete. Assessment of disease severity and management was mixed and results regarding testing for adenovirus and SARS-CoV-2 were inconsistent for both serological testing and testing of explant or biopsy liver samples. More recent studies suggest a more plausible role for adenovirus and/or adeno-associated virus 2.Conclusions and RelevanceThis systematic review without meta-analysis describes the challenge posed by hepatitis of unknown etiology in terms of investigation and management, with many cases progressing to acute liver failure. The lack of clarity regarding pathogenesis means that these children may be missing the potential for targeted therapies to improve outcomes and avert the need for transplant. Clinicians, immunologists, and epidemiologists must collaborate to investigate the pathogenesis of this novel hepatitis.

Multi‐country outbreak of severe acute hepatitis of unknown origin in children, 2022

“…The most likely assumption supported by the current data is that the normal HAdV infections were rendered more severe by an additional cofactor such as secondary immunodeficiencies resulting from other pathogens or drugs or toxins 1,15,23,24 . Among the possible contributing factors to acute liver failure in children, abnormal innate immunity (resulting in a lack of limiting inflammatory responses leading to propagation of hepatocyte damage), has been hypothesised to play a major role 5,8,44,46,47 …”

Acute hepatitis of unknown origin in children: A combination of factors

“…For children with acute hepatitis of unknown etiology but serum transaminases (ALT, AST) below 500 U/L, close attention should also be paid to their disease progression. If a mechanism associated with a postinfectious inflammatory process is identified, early administration of corticosteroids or immunomodulators may prevent progression to acute liver failure (Alexander and Deep, 2022).…”

An Old Acquaintance: Could Adenoviruses Be Our Next Pandemic Threat?

“…Two years after the COVID-19 pandemic, acute hepatitis of unknown etiology in children (AHUCD) began to be reported worldwide [ 233 ]. Alexander et al reviewed a total of 22 case-control studies describing identified 1643 unknown hepatitis, with 120 children (7%) receiving liver transplants and 24 deaths (1%) [ 234 ]. The role of HAdV as a causative factor for at least some cases was theorized early and remains relevant.…”