A new hypothesis emerges to explain the mysterious cases of hepatitis in children

Enlarge / Liver damage in a patient with chronic active hepatitis C. Getty | BSIP

Researchers in the UK have offered the most detailed and complex hypothesis yet to explain the explosion of mysterious cases of liver inflammation, or hepatitis, in young children, which has been worrying medical experts around the world for several months.

The cases were first discovered in April, when doctors noted an unusual cluster of hepatitis cases in young children in Scotland. The illnesses were not linked to any known cause of hepatitis, such as hepatitis viruses (A through E), making them unexplained. Although unexplained cases of pediatric hepatitis do occur from time to time, a report that month noted 13 cases in Scotland in two months, when the country would typically see fewer than four a year.

Since then, the World Health Organization has identified more than 1,000 probable cases in 35 countries. Of these cases, 46 required liver transplantation and 22 died. The Centers for Disease Control and Prevention has identified 355 cases in the United States. As of June 22, 20 cases in the United States have required liver transplantation and 11 have died.

The hypotheses to explain the cases are very varied. Some have suggested – particularly emphatically – that the cases could be sequelae of infection with the pandemic coronavirus, SARS-CoV-2. The CDC, meanwhile, released data that found there were no increases in pediatric hepatitis cases or liver transplants from pre-pandemic baselines, suggesting that unusual clusters may not represent a new phenomenon.

Combination of factors

But a common feature among the cases has been an adenovirus infection. Extremely common childhood viruses have appeared in many cases. As such, many hypotheses have implicated adenoviruses, but this too is confusing, as adenoviruses are not known to cause hepatitis in previously healthy children.

In two new reports, British researchers offer a new hypothesis that may be the clearest but most complex explanation. Their data suggests the cases may arise from co-infection of two different viruses – one of which could be an adenovirus and the other a hitchhiking virus – in children who also have a specific genetic predisposition to hepatitis.

In one of the new studies, involving nine initial cases in Scotland, researchers found that all nine children were infected with adeno-associated virus 2 (AAV2). It is a small non-enveloped DNA virus of the genus Dependoparvovirus. It can only replicate in the presence of another virus, often an adenovirus but also some herpesviruses. As such, he tends to travel with adenovirus infections, which peaked in Scotland when the puzzling hepatitis cases arose.

Most strikingly, while all nine cases in the hepatitis group were positive for AAV2, the virus was completely absent in three separate control groups. It was found in zero of 13 age-matched healthy control children; zero of 12 children who had adenovirus infection but normal liver function; and zero of 33 children hospitalized with hepatitis for other reasons.

This finding was supported by a separate study by researchers in London, which looked at 26 cases of unexplained hepatitis with 136 controls. He also found AAV2 in many cases of hepatitis, but in very few control cases.

Predisposition

The study of the nine cases in Scotland went further by looking at the genetics of the children. The researchers noted that eight of the nine children (89%) had a genetic variant of a human leukocyte antigen called