Recent acute hepatitis cases of unknown origin in children have been linked to the common adeno-associated virus 2 (AAV2) in two new studies led by researchers at UCL, Great Ormond Street Hospital for Children and the University of Glasgow.
The research also found no evidence of a direct link between the spike in hepatitis cases and SARS-CoV-2 infection, the cause of Covid-19.
Since April 2022, more than 1,000 children in 35 countries have developed jaundice and acute severe hepatitis of unknown origin.
In the UK, the majority of the 268 cases have been under the age of five years old, with nearly 40% of hospitalised cases (74 of 189) requiring admission to intensive care, including 12 who needed a lifesaving liver transplant.
Submitted to pre-print server medRxiv, the research found that AAV2 was present at high levels in all samples from patients with unexplained hepatitis. And the virus, which is not known to normally cause disease and often accompanies infection with adenoviruses – a separate class of common virus – has now been found by scientists to be associated with the development of acute hepatitis in a small number of young children.
Previously, health officials believed that a spike in adenovirus infections – which typically cause mild cold or flu-like illness – during spring 2022, may have been part of the explanation for the outbreak of hepatitis cases. This is because, until now, it was the most commonly found virus in samples from the affected children.
However, the two new studies show that typically ‘harmless’ AAV2, which cannot replicate without a “helper” virus such as adenovirus or herpesvirus, was present in 96% of cases of unknown hepatitis examined across both studies.
Consequently, the researchers believe that coinfection with two viruses – AAV2 and an adenovirus, or less often the herpesvirus HHV6 (which has also been found in sample from some patients) – may offer the best explanation for the onset of severe liver disease in affected children.
Professor Judith Breuer (UCL GOS Institute of Child Health) said: “While we still have some unanswered questions about exactly what led to this spike in acute hepatitis, we hope these results can reassure parents concerned about Covid-19 as neither teams have found any direct link with SARS-SoV-2 infection. Our data do, however, point to AAV2 in the liver and, or blood of cases as the strongest biomarker for the hepatitis.
“Additionally, the presence of HHV6 and adenovirus in the damaged livers, removed from the five children who needed liver transplants, raises questions as to the role of co-infections with these three viruses in the most severe cases.”
Dr Sofia Morfopoulou (UCL GOS Institute of Child Health) said: “The finding of AAV2 in 96% of the unexplained hepatitis patients but only rarely in the samples from the control populations, and at much lower viral titres, raises a lot of interesting questions.
“International collaborations to further investigate and elucidate the role of AAV2 and co-infecting viruses in paediatric unexplained hepatitis in patients from different countries are now needed.”
The two studies were led independently and simultaneously. One, examining cases from Scotland by the MRC-University of Glasgow Centre for Virus Research (CVR) and the Royal Hospital for Children in Glasgow, in partnership with Public Health Scotland and ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) WHO Clinical Characterisation Protocol UK (CCP-UK); and a second studying cases from across all four UK nations at UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, in partnership with the UK Health Security Agency.
With expertise in metagenomics and adenovirus sequencing, the London team studied 28 cases, including liver samples from five children that required a transplant and blood samples from the remaining children who did not – residual samples were sufficient to test 17 cases for AAV2 replication in the liver of children with unknown hepatitis.
Patient samples were compared with 132 controls from immunocompromised and immunocompetent patients. The London study showed that AAV2 was present only very rarely in the children who did not have hepatitis (6 out of 100) and at much lower levels, even for immunocompromised children (11 out of 32).
Researchers found no SARS-CoV-2 in the liver of patients, while tests conducted by the team in Glasgow to find out whether the children had previously had Covid-19 found that only two thirds of the patents had antibodies to the infection, similar to SARS-CoV-2 antibody prevalence in Scottish children at the time.
Additionally, the peak in cases occurred after the peak in Covid-19 cases in Scotland but only shortly after a peak in adenovirus infections.
Dr Antioa Ho (MRC-University of Glasgow Centre for Virus Research) said: “It is critical to interpret our findings in relation to the timeframe of the patients’ clinical presentation.
“Most of the Scottish children had a preceding illness with diarrhoea, vomiting and abdominal pain (often associated with adenovirus infection) between 1 to 11 weeks prior to presenting to hospital with acute liver inflammation, which may explain why adenovirus has not been identified in all affected children.
“The temporal association between adenovirus/ HHV6 and AAV2 infections requires further study.”
AAV2 is not an adenovirus but a member of the parvovirus family. Researchers found the virus at very high levels in the blood and liver of patients sampled, and it was also found to be replicating in the liver.
In contrast, AAV2 was absent or only present in very low levels in the blood and liver of the control groups of children who did not have acute hepatitis.