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 infection.
Submitted to MedRxiv as pre-prints, 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.
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 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.
Since April 2022, a number of young children worldwide have developed jaundice and acute severe hepatitis of unknown origin. Currently the World Health Organisation (WHO) has reported at least 1010 probable cases in 35 countries. Children with the condition have commonly had to be hospitalised for a number of days, 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 (74 of 189) requiring admission to intensive care.
Previously, health officials had thought that a spike in adenovirus infections in spring 2022 – until now the most commonly-found virus in samples from the affected children – may be part of the explanation for this spike in hepatitis cases. These two new studies shed light on another virus that seems to play a significant role.
Researchers across two teams found that AAV2 (which cannot replicate without a ‘helper’ virus such as an adenovirus or herpesvirus) was present in 96% cases of unknown hepatitis examined across both studies.
Therefore, the researchers believe that coinfection with two viruses – AAV2 and an adenovirus, or less often the herpes virus 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.
The Glasgow research and patient genetics
The Scottish study carried out a detailed investigation of nine cases and 58 control subjects. Using next-generation sequencing and real-time PCR, the research team compared samples and were able to confirm the presence of AAV2 in the plasma and liver of all nine cases. There was no AAV2 in any of the subjects in the control groups, which were made up of age-matched healthy controls, children with adenovirus but normal liver function and children admitted to hospital with known causes of hepatitis. The Scottish study also examined the genetics of the patients with unknown hepatitis, alongside the pathogen genomics, to find out whether any of the children may be 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 healthy children, or in the genes of children with other forms of hepatitis. The team believe these genetic sequences may offer another part of the answer as to why some children have become seriously unwell.
The London research, sequencing and immunocompromised patients
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, 16 of which tested positive. RNA sequencing of liver samples confirmed the presence of 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).
Unknown hepatitis and SARS-CoV-2
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, similar to SARS-CoV-2 antibody prevalence in Scottish children at the time. 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.
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