Study provides insights into child hepatitis outbreak

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A new study strongly suggests that infection with the common virus AAV2 - adeno-associated virus 2 - and an underlying genetic predisposition were associated with the onset of acute hepatitis in children.

Since April 2022, a number of young children worldwide have developed jaundice and acute severe hepatitis of unknown origin.

While the outbreak has now largely subsided, the World Health Organisation estimates there have been at least 1010 probable cases in 35 countries.

In the UK, the majority of the 270 cases were under the age of five years old, with many requiring admission to intensive care and 15 children requiring liver transplants as a result of their condition.

Common virus

AAV2 infects up to 90 per cent of the population. It is not known to normally cause disease and requires co-infection with certain viruses, such as adenoviruses, which can cause gastroenteritis as well as cold or flu-like symptoms.

The first detailed research investigation into the recent outbreak – involving University of Edinburgh scientists – has found that AAV2 was present in a range of different samples taken from children with acute unexplained hepatitis.

In contrast, AAV2 was not commonly found in samples taken from children in the control groups.

AAV2 may cause disease itself or it may be a useful biomarker of recent adenovirus infection which may be the main underlying pathogen, but can be harder to detect, according to experts.

The research builds on findings from two earlier UK studies, which first made the link between AAV2 and acute hepatitis in children. Now, with more patients, samples and controls, this updated peer-reviewed study offers important new data.

The study was led by researchers at the University of Glasgow in collaboration with the University of Edinburgh, the Royal Hospital for Children in Glasgow, Public Health Scotland and ISARIC (International Severe Acute Respiratory and emerging Infections Consortium), and the WHO Clinical Characterisation Protocol UK (CCP-UK).

Genetic link

The study also examined the genetics of patients with unknown hepatitis to find out whether any of the children may have been more susceptible to this type of acute hepatitis.

Using detailed genomic testing of the patients, researchers were able to identify differences in the Human Leukocyte Antigen gene that were not commonly found in the control groups of Scottish platelet donors or UK Biobank participants.

The Human Leukocyte Antigen gene is involved in helping the immune system distinguish between foreign invaders, such as viruses, and the body’s own cells. Experts say this genetic variant may offer another part of the answer as to why some children have become seriously unwell.

The study, published in the journal Nature, was funded by Public Health Scotland, the National Institute for Health Research (NIHR) and the Medical Research Council.

This is the best example I've seen of academic researchers working hand-in-glove with national public health agencies to tackle a new threat. Because we had the ISARIC4C study infrastructure in place before the outbreak, we were able to find strong evidence for the underlying cause of a completely new disease, within a few months of the first case being reported.

Professor Kenneth Baillie

There are many unanswered questions and larger studies are urgently needed to investigate the role of AAV2 in paediatric hepatitis cases, particularly the role of the immune response in the disease process.

Professor Emma Thomson

Related links

Read the paper in the journal Nature

ISARIC website

The two early pre-prints on the outbreak can be found below:

• Adeno-associated virus 2 infection in children with non-A-E hepatitis
• Genomic investigations of acute hepatitis of unknown aetiology in children