Extension / Liver lesions in patients with chronic active hepatitis C.
UK researchers have come up with the most detailed and complex hypothesis yet to explain the outbreak of mysterious cases of liver inflammation (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 were not related to any known cause of hepatitis, such as hepatitis viruses (A to E), so they were not explained. Although unexplained cases of pediatric hepatitis appear from time to time, a report that month noted 13 cases in Scotland in two months, when the country would normally see 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 identified 355 cases in the United States. As of June 22, 20 cases in the United States required liver transplants and 11 died.
The hypotheses to explain the cases have been very diverse. 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 that found there has been no increase in cases of pediatric hepatitis or liver transplants above pre-pandemic baseline levels, suggesting that the unusual groups 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 adenovirus, but this too is puzzling, because adenoviruses are not known to cause hepatitis in previously healthy children.
In two new reports, UK researchers offer a new hypothesis that may be the clearest but most complex explanation. Their data suggest that cases may arise from a coinfection 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, looking at nine early cases in Scotland, researchers found that all nine children were infected with adeno-associated virus 2 (AAV2). This 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, it tends to travel with adenovirus infections, which increased in Scotland when puzzling cases of hepatitis emerged.
announcement
Most strikingly, while all nine cluster hepatitis cases 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 an adenovirus infection but normal liver function; and zero of 33 children hospitalized with hepatitis for other reasons.
This finding was supported by an independent study led by researchers in London, which looked at 26 cases of unexplained 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 percent) 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 cases of hepatitis. In addition, HLA-DRB1*04:01 is already 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 cells T cells. This presentation trains T cells on how to respond to potential threats, triggering immune responses to invading germs 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: an adenovirus infection and an AAV2 infection, one of which triggers an aberrant immune response in genetically predisposed children. It is not clear exactly how all the factors combine, but according to the nine cases, all three factors are necessary. This could explain why hepatitis cases are so rare, linked to adenovirus infections, and seemed to cluster after pandemic restrictions were lifted, when many susceptible children became infected with common viruses, including adenoviruses.
Of course, this is just a hypothesis at the moment, and it’s mostly based on just nine cases from 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 analysis of larger cohorts of children and molecular research to understand the potential mechanism.