UK scientists have linked the rise in hepatitis in children to the common adeno-associated virus 2 (AAV2), which has been found at high levels in almost all samples of young patients with unexplained hepatitis.
Since January 2022, a number of young children worldwide have developed jaundice and acute severe hepatitis of unknown origin. Currently the World Health Organization (WHO) has reported at least 1,010 probable cases in 35 countries. Children with the condition have commonly had to be hospitalized 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 hospitalized cases (74 of 189) requiring admission to intensive care.
Hepatitis is an inflammation of the liver which is most commonly caused by a viral infection. The five main causes of viral hepatitis are hepatitis A, B, C, D and E, but AAV2 is not usually known to cause disease on its own and is usually accompanied by an adenovirus infection, a common virus that causes mild cold or flu-like illness.
Previously, health officials thought that a surge in adenovirus infections in the spring of 2022 (the virus most commonly found in samples of affected children so far) could be part of the explanation for the surge in hepatitis cases.
Researchers at the University of Glasgow looking at cases in Scotland and a second new study at Great Ormond Street Hospital (GOSH) that study cases across four UK countries sheds light on another virus that appears to be playing an important 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.”
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.
Professor Judy Breuer, Professor of Virology at UCL GOS ICH and Honorary Consultant Virologist at GOSH 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-CoV-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.”
“We at GOSH/UCL were very happy to contribute our specialist expertise which has been built-up to support children at GOSH, to help in the investigation of this global emergency, affecting children in the UK at the moment.”
Pamela Healy, chief executive at the British Liver Trust adds: “We have been concerned about the increase in hepatitis cases among children. While we are not seeing cases of this type of hepatitis among adults, the situation is being carefully monitored. We are keen to unite with partners so that we can raise awareness and children at risk can be identified early and tested. We also support any research into the causes and potential treatments so that further cases can be prevented or detected early and treated effectively.”
Dr Antonia Ho, Clinical Senior Lecturer and Consultant in Infectious Diseases at the 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.”
Dr Sofia Morfopoulou, Sir Henry Wellcome fellow at UCL GOS ICH and a computational statistician, 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 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.”
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.