Enlarge / Liver lesions in a patient with chronic active hepatitis C.
UK researchers have come up with the most detailed and complex hypothesis yet to explain an outbreak of mysterious cases of inflammation of the liver – also known as hepatitis – in young children, which has worried medical experts around the world for several months.
The cases first came to light in April when doctors noticed an unusual cluster of hepatitis cases in young children in Scotland. The illnesses are not associated with a known cause of hepatitis, such as hepatitis viruses (A to E), making them unexplained. Although unexplained cases of pediatric hepatitis do occur from time to time, a report this month notes 13 cases in Scotland in two months, when the country usually sees fewer than four in a year.
Since then, the World Health Organization has counted more than 1,000 probable cases from 35 countries. Of these cases, 46 required liver transplants and 22 died. The Centers for Disease Control and Prevention has identified 355 cases in the US. As of June 22, 20 cases in the US have required a liver transplant and 11 have died.
Hypotheses to explain the cases are wide-ranging. Some have suggested — particularly strongly — that the cases may be the result of infection with the pandemic coronavirus, SARS-CoV-2. Meanwhile, the CDC released data showing no increase in pediatric hepatitis cases or liver transplants above pre-pandemic baseline levels, suggesting the unusual clusters may not represent a new phenomenon.
A combination of factors
But a common feature among the cases is adenovirus infection. Extremely common children’s viruses have appeared in many cases. As such, many hypotheses involve adenoviruses, but this is also puzzling because adenoviruses are not known to cause hepatitis in previously healthy children.
In two new reports, UK researchers propose a new hypothesis that may be the clearest yet most complex explanation. Their data suggest that cases may arise from coinfection of two different viruses—one of which may be an adenovirus and the other a hitchhiker virus—in children who also have a specific genetic predisposition to hepatitis.
In one of the new studies looking at nine early 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 adenovirus, but also some herpes viruses. As such, it tends to travel with adenovirus infections, which increased in Scotland when the puzzling cases of hepatitis occurred.
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Most strikingly, while all nine cases of cluster hepatitis tested 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 in a separate study led by researchers in London, which looked at 26 unexplained cases of hepatitis with 136 controls. He also found AAV2 in many of the hepatitis cases but in very few of the control cases.
Predisposition
The study of the nine cases in Scotland went a step further by examining the children’s genetics. The researchers noted that eight of the nine children (89%) had a gene variant for a human leukocyte antigen called HLA-DRB1*04:01. But this gene variant is only found in around 16 per cent of Scottish blood donors, well below the frequency found in hepatitis cases. In addition, HLA-DRB1*04:01 is now known to be associated with autoimmune hepatitis and some cases of rheumatoid arthritis.
In general, human leukocyte antigen (HLA), also known as major histocompatibility complex or (MHC), are proteins outside immune cells that present antigen—such as viral or bacterial peptides—to T cells. This presentation teaches T cells how to respond to potential threats, triggering an immune response to invading microbes or tolerance to specific antigens. Thus, HLA proteins play a critical role in influencing immune responses.
The Scottish study suggests that all three factors combine to explain the hepatitis cases: adenovirus infection and tag-along AAV2 infection, one of which triggers an abnormal immune response in genetically predisposed children. It is unclear exactly how all the factors combine, but based on the nine cases, all three factors are necessary. This may explain why hepatitis cases are so rare associated with adenovirus infections and seem to cluster after pandemic restrictions are lifted, when many susceptible children become infected with common viruses, including adenoviruses.
Of course, this is just a hypothesis for now—and one based primarily on just nine cases in a study that hasn’t yet been peer-reviewed. Researchers will need to do much more work to determine whether this hypothesis explains the cases, including looking at larger cohorts of children and molecular studies to understand the potential mechanism.
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