Global Expansion of Acute Hepatitis Outbreaks in Healthy Children

May 5, 2022

Introduction 

A recent rise in acute hepatitis among children is expanding globally. The UK first reported an unexpected, significant increase in cases of severe acute hepatitis of unknown origin in previously healthy children. According to the WHO (1), as of 21 April 2022, at least 169 cases of acute hepatitis have been reported from 11 countries: the UK and Northern Ireland (114 cases), Spain (13), Israel (12), the US (9), Denmark (6), Ireland (<5), The Netherlands (4), Italy (4), Norway (2), France (2), Romania (1), and Belgium (1). Cases are aged 1 month to 16 years old, mainly affecting children between the ages of 3–5 years. Many cases reported gastrointestinal symptoms, including abdominal pain, diarrhea and vomiting preceding presentation with severe acute hepatitis, and increased levels of liver enzymes (serum transaminase >500 IU/L (AST or ALT)). Seventeen children (~10%) have required liver transplantation; at least one death has been reported. Currently, the causative agent of the outbreak is under investigation. Adenovirus has been detected in at least 74 cases (where typing has been available, 18 cases have been identified as serotype 41). In addition, SARS-CoV-2 and a SARS-CoV-2 and adenovirus co-infection were identified in 20 and 19 cases, respectively. The common viruses that cause acute viral hepatitis (hepatitis viruses A, B, C, D and E) have not been detected in any of these cases. WHO and US Centers for Disease Control and Prevention (CDC) are investigating a possible connection between the hepatitis cases and adenovirus (1, 2). Notably, affected children have not received the COVID-19 vaccine, thus clarifying that this is not a side effect from the vaccine.

Adenovirus

The UK and the Netherlands have recently observed an increase in adenovirus infections in the community following low levels of circulation earlier in the COVID-19 pandemic, particularly in children under 5 years of age (3, 4). In fact, case numbers in March 2022 have returned to pre-pandemic peaks in some places (5). Human adenoviruses are a group of double-stranded nonenveloped DNA viruses belonging to the genus Mastadenovirus of the Adenoviridae family. Currently, 51 serotypes of human adenovirus are recognized with classification into species A to G. Human adenoviruses cause disease mainly in airways (species A, B, C and E), eyes (species B, C, D and E), urinary tract (species B) and gastrointestinal tract (species A, C, D, F, G) (6). Most human adenoviruses exhibit a broad tropism and are often associated with respiratory diseases. However, enteric species F exclusively causes gastroenteritis and is a major cause of infantile gastroenteritis worldwide, contributing to 5%-20% of hospitalizations for childhood diarrhea (7-9). These viruses also grow poorly in most cell culture systems, thus designating as “noncultivable” or “fastidious” adenovirus (10). The implicated adenovirus type 41 in the outbreak of acute hepatitis belongs to species F, typically causing diarrhea and vomiting and has not previously been linked to acute hepatitis as observed with these outbreaks (2). Adenovirus infection as a cause of severe hepatitis has been reported in immunocompromised adults and children (11-13), but is rare in immunocompetent children (14). There are two leading hypotheses linked to adenovirus: (1) circulation of a new variant is facilitating liver inflammation and (2) a routinely circulating variant is severely impacting immunologically naïve children following the enforcement of pandemic restrictions (1, 3, 5).

According to the WHO (1), as of 21 April 2022, at least 169 cases of acute hepatitis have been reported from 11 countries: the UK and Northern Ireland (114 cases), Spain (13), Israel (12), the US (9), Denmark (6), Ireland (<5), The Netherlands (4), Italy (4), Norway (2), France (2), Romania (1), and Belgium (1).
SARS-CoV-2 and a SARS-CoV-2 and adenovirus co-infection were identified in 20 and 19 cases, respectively.
The UK and the Netherlands have recently observed an increase in adenovirus infections in the community following low levels of circulation earlier in the COVID-19 pandemic, particularly in children under 5 years of age (3, 4).

Conclusion

Other infectious and non-infectious causes of acute hepatitis remain possibilities. Information on epidemiological and risk factors and genomic sequencing data are required for a comprehensive analysis to identify the source of acute hepatitis. WHO recommends the testing of blood, serum, urine, stool, and respiratory samples, as well as liver biopsy samples (when available), with further virus characterization (1). Identifying the the cause of this acute hepatitis is a priority to efficiently control and determine preventive measures. Maintaining personal hygiene practices, such as regular hand washing, disinfection of contact surfaces, and mask wearing, can aid the protection of children.

Our GVN Team thanks Drs. Antonia Ho and Massimo Palmarini (The MRC-University of Glasgow Centre for Virus Research, UK) for reviewing this manuscript and for providing us with invaluable comments and insights.

References

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