Spike in Hepatitis Cases Linked to Adeno-Associated Virus 2

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In two new research papers, scientists have identified a link between recent cases of acute hepatitis in children and adeno-associated virus 2 (AAV2). The studies suggest a co-infection with AAV2 and another virus, such as adenovirus, may be the cause of the increase in cases. The data is published on the pre-print server MedRxiv.^1,2

Spike in hepatitis cases

An outbreak of acute severe hepatitis and jaundice of unknown origin in children was first detected on April 5. A World Health Organization (WHO) news release states that, as of July 8, 1,010 probable cases have been reported across 35 countries. Almost 50% of these cases have been reported in Europe, including 272 from the United Kingdom, and 435 cases occurred in the Region of the Americas. The majority (76%) of cases are presenting in children under the age of six, with the condition seemingly affecting both males and females equally.

According to the WHO, some children presenting with the condition have required hospitalization, admission to intensive care and, in some cases, a liver transplant. The organization has launched a global investigation, including an online survey, to gather data on the public health situation.

Scientists have rapidly assembled to explore the underlying cause of the spike in hepatitis cases. A proposed hypothesis was that adenovirus – a common virus that causes respiratory symptoms, vomiting and diarrhoea – could be the culprit, due to a recent increase in reported cases. Typically, infections with adenoviruses do not result in serious illness. However, hepatitis has been detected in some immunocompromised individuals that have been infected with the virus. Considering that the reported cases of acute severe hepatitis so far have occurred in previously healthy children – i.e., not immunocompromised – this hypothesis could not be confirmed.

Two new preprint studies, one analyzing patients from Scotland, and the other studying patient cases from all four UK nations, have now shed some light on a potential association with another virus – AAV2.

Does genetics play a role in susceptibility?

Researchers at the MRC-University of Glasgow Centre for Virus Research (CVR) and the Royal Hospital for Children in Glasgow used next-generation sequencing and real-time PCR to analyze samples from 9 patients with confirmed acute hepatitis from an unknown cause and 58 control subjects. The control group included age-matched healthy children, children that had adenovirus infection and children admitted to hospital with a known cause of hepatitis.

The researchers identified the presence of AAV2, a member of the parvovirus family, in the plasma and livers of all hepatitis patients – a finding that was not replicated in the control group.

In their genetic analysis, the research team also discovered a variation in the Human Leukocyte Antigen (HLA) gene, a complex that encodes the proteins required for antigen production, in the cases of severe acute hepatitis of unknown cause. This variation was not identified in the samples from the control group, which led the researchers to suggest that genetics may contribute to how susceptible a child is to developing acute severe hepatitis.

Association with AAV2 also identified in London study

A second study exploring cases of acute severe hepatitis took place at Great Ormond Street Hospital and the UCL Great Ormond Street Institute of Child Health (UCL GOS ICH), in partnership with the UK Health Security Agency. This research was conducted at the same time as the study in Scotland, but was not a collaboration.

Focusing on 28 cases of acute severe hepatitis of unknown cause, the researchers were able to collect liver samples from five children that had required a transplant, and blood samples from the remaining participants. Samples from 17 cases were of sufficient quality to test for the presence of AAV2, with 16 samples testing positive.

Applying RNA sequencing, the researchers confirmed AAV2 replication in the livers of children presenting with unknown causes of hepatitis. The samples were compared with 132 control samples obtained from individuals that were immunocompromised and/or immunocompetent. AAV2 was found only rarely in children without hepatitis (6 patients out of 100), and at lower levels even in children that were immunocompromised (11 patients out of 32).

AAV2 requires “replication assistance”

Collectively, the research studies demonstrate an association between the presence of AAV2 and unexplained hepatitis in children. AAV2 is a virus that cannot replicate without “help” from another virus (sometimes an adenovirus or more rarely, herpes virus, which was identified in some patients across the two studies). The scientists suggest that coinfection with another virus – such as adenovirus – is therefore the “best explanation” for why some children are developing severe liver disease.

“AAV2 may cause disease itself or it may be a useful biomarker of recent adenovirus infection, which may be the main underlying pathogen, but which can be harder to detect,” Professor Emma Thomson, clinical professor and consultant in infectious Diseases at the MRC-University of Glasgow CVR and senior author of the Scottish study, said.

“The finding of AAV2 in 94% of the unexplained hepatitis patients but only rarely in the samples from the control populations, and at much lower viral titers, raises a lot of interesting questions. International collaborations to further investigate and elucidate the role of AAV2 and co-infecting viruses in pediatric unexplained hepatitis in patients from different countries are now needed,” Dr. Sofia Morfopoulou, Sir Henry Wellcome fellow at UCL GOS ICH and a computational statistician, said.

The research studies also demonstrated that there is no evidence to suggest a recent or previous infection with SARS-CoV-2 could be causing acute hepatitis. SARS-CoV-2 was not detected in liver samples, and the study conducted in Glasgow found that only two thirds of patients had detectible SARS-CoV-2 antibodies.

Lockdown’s effect on the immune system

Exactly why the spike in cases seems to be occurring now is a question that remains to be answered. Both teams have acknowledged that increased cases of adenovirus infection post-lockdown could be one explanation, as immune systems may be lower in some children, but more work is needed.

“Larger studies are urgently needed to investigate the role of AAV2 in pediatric hepatitis cases,” Thomson said.

As pre-prints, the studies require peer review, which should be noted. However, the teams have received praise for their ability to respond quickly to the outbreak. “This project is an excellent example of how rapid collaboration between leading virology and clinical experts […] is uncovering the likely cause of the recent outbreak of acute viral hepatitis in young children. These two studies pave the way towards understanding why these children have become severely unwell,” Dr. Anna Kinsey, head of epidemic preparedness at the Medical Research Council, which part-funded the research, said.

References:

1. Morfopoulou S, Buddle S, Torres Montaguth OE, et al. Genomic investigations of acute hepatitis of unknown aetiology in children. Medrxiv. Preprint published online July 26 2022. Accessed July 26 2022. https://media.gosh.nhs.uk/documents/MEDRXIV-2022-277963v1-Breuer.pdf.

2. Ho A, Orton R, Tayler R, et al. Adeno-associated virus 2 infection in children with non-A-E hepatitis. Medrxiv. Preprint published online July 26 2022. Accessed July 26 2022. https://www.medrxiv.org/content/10.1101/2022.07.19.22277425v1.