Researchers in the UK have come up with the most detailed and complex hypotheses yet to explain the outbreak of mysterious cases of hepatitis – also known as hepatitis – in young children, which has alarmed medical experts around the world for months.
The cases first emerged in April, when doctors noticed an unusual cluster of hepatitis cases in young children in Scotland. The diseases were not related to any known cause of hepatitis, such as hepatitis A to E viruses, making them unexplained. Although unexplained cases of hepatitis in children do appear from time to time, a report that month noted 13 cases in Scotland in two months when the country was seeing fewer than four cases a year.
Since then, the World Health Organization has counted more than 1,000 probable cases from 35 countries. Of those cases, 46 required a liver transplant, and 22 died. The Centers for Disease Control and Prevention identified 355 cases in the United States. As of June 22, 20 US cases have required liver transplants, and 11 have died.
Hypotheses to explain the cases were extensive. Some have suggested – particularly rigorously – that the cases may be after-effects of infection with the pandemic coronavirus, SARS-CoV-2. Going forward, the CDC has published data that found there was no increase in pediatric hepatitis cases or liver transplants from pre-epidemic baseline levels, suggesting that unusual combinations may not represent a new phenomenon.
combination of factors
But the common feature between the cases was infection with an adenovirus. Very common childhood viruses have appeared in many cases. As such, many hypotheses have involved adenoviruses, but this is also puzzling, because adenoviruses note It is known to cause hepatitis in previously healthy children.
In two new reports, British researchers present a new hypothesis that may be the clearest and most complex explanation. Their data suggests that the cases may arise from co-infection of two different viruses — one that may be an adenovirus and the other a worm — in children who also have a specific genetic predisposition to hepatitis.
In one new study, looking at nine early-stage cases in Scotland, researchers found that all nine children were infected with adeno-associated virus 2 (AAV2). This is a small DNA virus that is not encapsulated in Dependoparvovirus sex. It can only multiply in the presence of another virus, most often adenoviruses but also some herpes viruses. As such, it tends to travel with adenovirus infections, which spiked in Scotland when baffling hepatitis cases surfaced.
Most strikingly, while all nine cases of hepatitis were AAV2-positive, the virus was completely absent in three separate control groups. It was found in zero of 13 age-matched healthy children; Zero out of 12 children had adenovirus infection but normal liver function; And 33 children were not hospitalized with hepatitis from other causes.
This finding was supported in a separate study led by researchers in London, which looked at 26 cases of unexplained hepatitis with 136 control groups. AAV2 was also found in many cases of hepatitis, but in very few control cases.
The study of the nine cases in Scotland went a step further by examining the genes of the children. The researchers noted that eight of the nine children (89 percent) had a human leukocyte antigen gene variant called HLA-DRB1*4:01. But this type of gene is only present in about 16 percent of blood donors in Scotland, which is much lower than the frequency found in cases of hepatitis. Furthermore, it is already known that HLA-DRB1*4:01 is 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 of immune cells that present antigen – such as viral or bacterial peptides – to T cells. This display trains T cells how to respond to potential threats, triggering immune responses to invading germs or carrying specific antigens. Thus, HLA proteins play an important role in influencing immune responses.
The Scottish study suggests that the three factors combine to explain cases of hepatitis: adenovirus infection and infection of the marker along AAV2, one of which leads to an aberrant immune response in children with a genetic predisposition. It is unclear how exactly all the factors combine, but based on the nine cases, all three factors are necessary. This may explain why cases of hepatitis, associated with adenovirus infection, are rare and clustered after epidemiological restrictions were lifted, when many susceptible children were infected with common viruses, including adenoviruses.
Of course, that’s just a hypothesis at the moment – and one that’s primarily based on just nine cases in a study that has yet to be reviewed. We will have to do more work to determine if this hypothesis explains the cases, including looking at larger groups of children and researchers with molecular research to understand the potential mechanism.