Researchers in the UK have put forward the most detailed and complex hypothesis yet to explain the outbreak of mysterious cases of liver inflammation – also known as hepatitis – in young children that has worried medical experts worldwide for several months.
The cases first came to light in April, when doctors noted an unusual rise in hepatitis cases among young children in Scotland. The diseases were unrelated to a known cause of hepatitis, such as B. Hepatitis (A to E) viruses, which makes them unexplained. Although unexplained cases of pediatric hepatitis do occur from time to time, a report this month said 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 counted more than 1,000 probable cases from 35 countries. Of these cases, 46 required liver transplantation and 22 died. The Centers for Disease Control and Prevention identified 355 cases in the USA. From June 22nd 20 US cases required liver transplants and 11 died.
Hypotheses to explain the cases were far-reaching. Some have suggested – particularly adamantly – that the cases could be after-effects of infection with the pandemic coronavirus SARS-CoV-2. The CDC, meanwhile, released data showing that there has been no increase in pediatric hepatitis cases or liver transplants above pre-pandemic baseline levels, suggesting the unusual clusters may not represent a new phenomenon.
combination of factors
However, a common feature of the cases was infection with an adenovirus. The extremely common childhood viruses have emerged in many cases. Therefore, many hypotheses have involved adenoviruses, but this is also puzzling because adenoviruses are Not It is 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 suggest that the cases could arise from co-infection of two different viruses – one of which may be an adenovirus and the other a hitchhiker virus – in children who also happen to have a specific genetic predisposition to hepatitis.
in the one of the new studiesStudying 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 in the dependoparvovirus Genus. 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 rose sharply in Scotland when the enigmatic cases of hepatitis hit.
Most strikingly, while all nine cases of hepatitis clusters were positive for AAV2, three separate control groups were completely absent of the virus. It was found in zero out of 13 age-matched healthy control children; null of 12 children with adenovirus infection but normal liver function; and 0 of 33 children hospitalized with hepatitis for other reasons.
This finding was in a separate study led by researchers in London who studied 26 unexplained hepatitis cases with 136 controls. It also found AAV2 in many of the hepatitis cases but in very few of the control cases.
The investigation into the nine cases in Scotland went a step further by examining the children’s genetics. The researchers found 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 hepatitis cases. In addition, it is already known that HLA-DRB1*04:01 is linked to HLA-DRB1*04:01 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 presentation trains T cells to respond to potential threats by eliciting immune responses to invading germs or tolerance to specific antigens. Thus, HLA proteins play a crucial role in influencing immune responses.
The Scottish study suggests that all three factors together explain the cases of hepatitis: adenovirus infection and AAV2 infection, one of which triggers an aberrant immune response in children with a genetic predisposition. It is unclear exactly how all the factors are combined, 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 appear to be increasing after pandemic restrictions were lifted, when many susceptible children became 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 has yet to be peer-reviewed. Researchers need to do much more work to determine if this hypothesis explains the cases, including looking at larger cohorts of children and doing molecular research to understand the potential mechanism.
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