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Characterization of a Hepatitis Outbreak in Children, 2021 to 2022

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What is the available evidence regarding cases of hepatitis of unknown etiology in children in 2021 to 2022?

Findings  This systematic review without meta-analysis identified 1643 cases across 22 studies, with 120 children (7%) receiving liver transplants and 24 deaths (1%). Testing focused on adenovirus, SARS-CoV-2, and adeno-associated virus 2.

Meaning  These findings suggest that the cause of novel hepatitis in children remains undetermined, but the potential role of adenovirus, adeno-associated virus 2, and SARS-CoV-2 requires further exploration in multicenter collaborative studies.


Importance  After 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.

Objective  To summarize the currently available evidence regarding novel pediatric hepatitis of unknown etiology (or novel hepatitis), encompassing case numbers, testing, management, and outcomes.

Evidence Review  A 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.

Findings  A 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 Relevance  This 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.

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Article Information

Accepted for Publication: August 31, 2022.

Published: October 18, 2022. doi:10.1001/jamanetworkopen.2022.37091

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Alexander EC et al. JAMA Network Open.

Corresponding Author: Akash Deep, MD, Professor, Paediatric Intensive Care Unit, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom (akash.deep@nhs.net).

Author Contributions: Drs Alexander and Deep had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Alexander.

Supervision: Deep.

Conflict of Interest Disclosures: Dr Deep reported serving as chair of Scientific Affairs and chair of the Liver Failure Working Group of the European Society of Pediatric and Neonatal Intensive Care. No other disclosures were reported.

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