The mystery around the rash of acute, serious hepatitis cases that have afflicted over 1000 children under the age of 16 may have been unravelled by a group of Scottish researchers who say that the interaction of two common adenoviruses, or related herpes viruses, may have caused the condition in genetically susceptible children who failed to build up the usual immunity due to COVID lockdowns – and then fell seriously ill after they began to mix socially again.

Their study, led by a team from the University of Glasgow’s Center for Virus Research, and supported by others from University College London and Public Health Scotland, was published on the preprint server medrxiv.org last week.

Over 1000 children in 35 countries, many under the age of 5, have fallen victim to the acute severe acute hepatitis of unknown aetiology, as WHO has termed it.  The most seriously ill have required liver transplants.

In a detailed investigation of nine Scottish children who had become acutely ill, researchers found that all of them were co-infected both with adeno-associated virus (AAV2), as compared with zero of healthy, aged matched child controls.

But the nine acutely ill children also were co-infected either with adenovirus (HAdV-41 or HAdV-C), which causes common colds or gastro-intestinal illness, or herpesvirus 6B (HHV6B), the research team found.

The nine children investigated also displayed a higher-than-usual frequency of a genetic variant of the human leukocyte antigen (HLA), known as HLA-DRB1.  The HLA genetic anomaly, which is associated with a range of other immune disorders, which may have made them more vulnerable to such diseases, the researchers said.

Serious illness link to lack of immunity

Typically, AAV2 is asymptomatic and it requires the presence of either either HAdV or a herpes virus to replicate.

But the co-infections may have occurred, and then caused the genetically susceptible children to become seriously ill, because they had not built up the required immunity to such infections more gradually during the period of COVID lockdowns, the researchers said.

“The recent clustering of cases may have arisen in part because of changes in exposure patterns to HAdV, AAV2 and HHV6B as a result of the COVID-19 pandemic,” the researchers concluded in their preprint, which has not yet been peer-reviewed.  “Faecal HAdV usually follows seasonal trends with maximal rates of detection in younger age groups. However, the circulation of respiratory viruses was interrupted in 2020 by the implementation of non-pharmaceutical interventions, including physical distancing and travel restrictions, instituted to mitigate SARS-CoV-2 transmission.

“These measures may have created a pool of susceptible younger children, resulting in much higher rates of HAdV and potentially AAV2 circulation in this population of naïve children when the COVID-19 restrictions were relaxed.”

Scientists studying the mysterious issue reacted with glee to the publication of the initial findings.  “It explains a LOT,” said CJ Houldcroft of Cambridge University’s Department of Medicine, in a Twitter string.

“This would explain A. the timing of the surge in cases in children, B. why not all children develop this rare complication and C. why the risk isn’t evenly distributed around the world (because of both pathogen exposure factors AND differences in genetic background),” she added, also noting that, AAV2 is part of a class of enteric adenoviruses that are “really common worldwide, including on people’s hands if they don’t wash them properly…11% of hands, yuck!.”

I love this preprint on non-A-E hepatitis. If it can be replicated in a bigger cohort, it explains a LOT: you seem to need two viruses to be present AND carry a genetic variant associated with auto-immune hepatitis risk https://t.co/mNpJkpVIk4

— Dr CJ Houldcroft 🕷️ (@DrCJ_Houldcroft) July 25, 2022

The University of Glasgow’s Professor Emma Thomson, who led the research, said, however, that there were still many unanswered questions. “Larger studies are urgently needed to investigate the role of AAV2 in paediatric hepatitis cases,” she told the BBC.

Image Credits: Paul Owere/Twitter , WHO, Dilemma Online/Twitter .