Recent acute hepatitis cases of unknown origin in children have now been linked to the virus AAV2 in two new UK studies, with no evidence of a direct link to SARS-CoV-2 (coronavirus) infection.
Both studies found that the common virus AAV2 (adeno-associated virus 2) was present at high levels in all samples from patients with confirmed cases of unexplained hepatitis. The virus, which is not known to normally cause disease and often accompanies infection with adenoviruses, has now been found by scientists to be associated with the development of acute hepatitis in a small number of young children.
Since April 2022, several young children worldwide have developed jaundice and acute severe hepatitis of unknown origin. Currently the World Health Organisation (WHO) has reported at least 1,010 probable cases in 35 countries. Children with the condition have commonly had to be hospitalised, with 11 children in England and one in Scotland requiring a liver transplant. In the UK, the majority of the 268 cases have been under the age of five years old with nearly 40% of hospitalised cases requiring admission to intensive care.
Previously, health officials had thought that a spike in adenovirus infections in spring 2022 may be part of the explanation for this increase in hepatitis cases. These two new studies shed light on another virus that seems to play a significant role.
The researchers found that AAV2 was present in 96% of cases of unknown hepatitis examined across both studies. AAV2 cannot replicate without a ‘helper’ virus such as an adenovirus or herpesvirus; therefore, the researchers believe that coinfection with two viruses – AAV2 and an adenovirus, or less often the herpes virus HHV6 – may offer the best explanation for the onset of severe liver disease in affected children.
The University of Glasgow’s and the Royal Hospital for Children in Glasgow, in partnership with Public Health Scotland and ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) and WHO Clinical Characterisation Protocol UK (CCP-UK), examined cases from Scotland.
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, examined cases from all four UK nations.
Unknown hepatitis and SARS-CoV-2 (coronavirus)
Both studies were able to rule out the likelihood of recent or prior SARS-CoV-2 infection as a direct cause for the acute hepatitis. 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 patients had antibodies to the infection. Further, the peak in cases occurred well after the peak in COVID-19 cases in Scotland but only shortly after a peak in adenovirus infections.
Researchers still cannot be certain why this is happening now, but both teams have highlighted the possibility that a peak in adenovirus infections in the general population after a period of lockdown may have contributed to this, through lowered immunity in children to certain viruses and changes in patterns of virus circulation.
, Clinical Professor and Consultant in Infectious Diseases at the CVR and senior author of the Scottish study said: “The presence of the AAV2 virus is associated with unexplained hepatitis in children. 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.
“There are many unanswered questions and larger studies are urgently needed to investigate the role of AAV2 in paediatric hepatitis cases. We also need to understand more about seasonal circulation of AAV2, a virus that is not routinely monitored – it may be that a peak of adenovirus infection has coincided with a peak in AAV2 exposure, leading to an unusual manifestation of hepatitis in susceptible young children.”
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.
