The recent spate of unexplained hepatitis infections in young children appears to be caused by two viruses working in cahoots with one another, according to two new studies conducted in the UK. Previously, health officials had suspected the outbreak may have been linked to a spike in adenovirus cases earlier this year, although the new studies indicate that adeno-associated virus 2 (AAV2) is also involved.
Since October 2021, the World Health Organization has reported 1,010 cases of “severe acute hepatitis of unknown aetiology in children”, with the majority occurring since April of this year. So far, 46 children have required liver transplants and 22 have died from the mysterious illness.
The two new studies – both of which are available as pre-prints as they await peer review – used next-generation sequencing techniques to search for the cause of the illness. Across both cohorts, 96 percent of patients tested positive for AAV2, while the virus was only rarely detected in those who didn’t suffer from the illness.
Not normally producing any negative health effects on its own, AAV2 requires the presence of another “helper” virus to replicate. The researchers believe that the onset of liver disease is caused by co-infection with AAV2 and adenovirus, or possibly the herpes virus HHV6.
“The presence of the AAV2 virus is associated with unexplained hepatitis in children,” said Professor Emma Thomson, senior author of one of the studies. “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.”
Thomson’s study examined nine cases in Scotland, detecting AAV2 in the blood and liver of every patient tested. In contrast, the virus was not present in any of the 58 controls, which included 13 healthy children, 12 children with adenovirus infection but no signs of hepatitis, and 33 children with other forms of hepatitis of known origin.
The second study looked at 28 cases across the UK, including five that had required a liver transplant.
“In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers,” write the authors. “AAV2 was also detected at high levels in blood from 10/11 nontransplanted cases.”
This finding was then compared to a control group of 100 kids without hepatitis, only six of whom tested positive for AAV2.
While it is still unclear how the viruses work together to trigger the illness, it is now evident that the mysterious outbreak is completely unrelated to COVID-19. Neither research team found traces of the SARS-CoV-2 virus in any of the patients, and the Scottish study revealed that around two-thirds of mystery hepatitis sufferers had COVID-19 antibodies – equal to that of the general population, indicating that the outbreak is unconnected to the pandemic.
However, the researchers do suggest that the spike in childhood hepatitis may be linked to lockdowns, as infants who were prevented from mixing with other kids might not have been exposed to either AAV2 or adenovirus, so would not have developed antibodies against them. As restrictions were then lifted, some children may have suddenly come into contact with multiple viruses within a short timeframe, allowing these pathogens to combine and trigger serious illness.
“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,” said Thomson.
“There are many unanswered questions and larger studies are urgently needed to investigate the role of AAV2 in paediatric hepatitis cases.”