New studies offer theory on cause of unusual hepatitis cases in children

JHere’s a new theory about what can cause puzzling cases of pediatric hepatitis of unknown origin — and it’s complex.

Two new, yet unpublished studies from scientists in the UK theorize that children who developed cases of hepatitis may have been co-infected with two different viruses and had a genetic predisposition to have an overly exuberant immune response when this happened. is produced. .

Previously, the main hypothesis was that adenovirus 41, which had been found in a number of infected children, caused liver damage. Adenovirus 41 is known to cause liver damage in immunocompromised children, but it has never been observed in children with intact immune systems.

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But the new studies report finding the presence of something called adeno-associated virus 2 – AAV2 for short – in the blood and liver tissue of a number of affected children. They also discovered that the children were infected with adenoviruses or herpes viruses.

Adeno-associated virus 2 is called a dependent parvovirus. It cannot replicate in a host’s cells unless another virus is present.

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If correct, that theory doesn’t rule out the possibility that adenovirus 41 played a role in the cases, said Angela Rasmussen, a virologist at the University of Saskatchewan’s Vaccine and Infectious Disease Organization.

“This suggests that AdV 41 (or another helper virus) is necessary but not sufficient,” she told STAT via email.

“If this is correct,” she added, “you need the combination of all three” – a helper virus, such as adenovirus 41, adeno-associated virus 2, and genetic predisposition.

In fact, Judy Breuer, lead author of one of the papers, said the group strongly believes that adenovirus – primarily but not exclusively adenovirus 41 – is involved. “We are very certain that the adenovirus is playing a role in one way or another,” Breuer, a clinical virologist at University College London and consultant at Great Ormond Street Hospital for Children, told STAT in an interview. .

Adeno-associated viruses aren’t usually looked for when clinicians try to determine the cause of a disease, she said, because they haven’t been considered harmful. But his group cast a very wide net when studying samples from some of the children in the outbreak, not looking to see if a particular pathogen was present, but to get a picture of all possible pathogens. that their samples contained.

She cautioned, however, that it’s still possible that AAV2 is a bystander, and not part of the cause, of these hepatitis cases.

Meanwhile, the second group of scientists, who are mostly from Scotland, have looked at the genetic makeup of a group of affected children there. Eight of the nine children studied had a particular genetic variant that affects how the immune system reacts to a threat. Almost 16% of Scottish blood donors carry this genetic mutation. Scottish doctors were among the first to report the unusual cases of hepatitis in the spring.

“The fact that these children had this particular immune genetic makeup…we hypothesize that this made them susceptible to further overreaction to one or both viruses,” Breuer said.

Mario Koopmans, head of the department of viroscience at Erasmus Medical Center in Rotterdam, the Netherlands, said the theory deserved further investigation, but was inconclusive at this stage. This “suggests there is something in the combination of AAV2 and Adeno or possibly other viruses,” she said in an email.

New studies still have to go through peer review. But if correct, they will help explain why some medical centers that treat children with liver disease have seen what appears to be an unusual number of cases of unexplained hepatitis from last fall through November. spring.

More than 1,000 such cases in 35 countries have been reported to the World Health Organization. Of this total, 22 children died and 46 required liver transplants. In the United States, 355 possible cases are under investigation, according to the Centers for Disease Control and Prevention. By the end of June, 20 of these children had needed liver transplants and 11 had died.

The studies also suggested that the disruption to normal life triggered by the pandemic may have contributed to increased transmission of adeno-associated virus 2 and adenoviruses when Covid-19 control measures began to ease, as more children would have been sensitive to it. This, in turn, would have led to an increase in the number of cases of hepatitis in children.

“The current outbreak follows the easing of restrictions due to the pandemic and represents one of many infections, including other enteric pathogens such as norovirus, which have occurred in UK children after the back to normal. [social] mixture,” wrote Breuer and his co-authors.

Koopmans accepted. “The combination of two viruses and a genetic susceptibility factor fits the hypothesis that the elevation in the number of cases became visible due to the unusual occurrence of ‘common’ infections, as the patterns of multiple viruses endemic diseases have been disrupted by COVID 19 control measures”.

Alasdair Munro, clinical research fellow in pediatric infectious diseases at Britain’s University Hospital Southampton, found the papers compelling.

“Everything seems to be fine, it will be interesting to see if further examination can confirm this is the cause – hopefully putting some of the debates to bed,” he wrote on Twitter.

But Rasmussen warned there were other pieces of the puzzle to be found, including how this trio of factors would cause the damage seen.

“I think the important things to keep in mind here are that this is about correlation, not causation,” she wrote. “More work will be needed to establish that this is the cause, including determining the mechanism.”

She also suggested that it would be good if other groups could replicate the results seen in these two groups of children from the UK “I hope that all other investigators who have reported these cases outside the UK check their sequence data for AAV2 sequences as well as do… genotyping.

The unexplained cases of pediatric hepatitis sparked a heated and even ugly debate on Twitter, with a number of scientists and doctors insisting that those investigating the apparent outbreak were ignoring what appeared to be obvious – that the illness was likely a consequence of a previous Covid infection.

Efforts to determine what was behind the cases – and whether there was indeed an ongoing outbreak – were complicated by the fact that data from the United States showed there had been no increased pediatric hepatitis of unknown origin, or liver transplants for children. hepatitis, even adenovirus 41 infections in the past year compared to before the pandemic. This does not mean that there may not have been an increase in cases caused by this constellation of triggers, just that the total number of cases of pediatric hepatitis for which a cause has not been found did not change.

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