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

There is a new theory about what may be causing puzzling cases of pediatric hepatitis of unknown origin — and it is complex.

Two new and as-yet-unpublished studies from scientists in the United Kingdom theorize that children who have developed the hepatitis cases may have been co-infected with two different viruses and had a genetic predisposition to have an over-exuberant immune response when that happened.

Previously the leading hypothesis was that adenovirus 41, which had been found in a number of the infected children, was causing the liver damage. Adenovirus 41 has been known to trigger liver damage in immunocompromised children, but had never been seen to do so in children with intact immune systems.

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

Adeno-associated virus 2 is what is known as a dependoparvovirus. It cannot replicate in a host’s cells unless another virus is present.

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

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

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

In fact, Judy Breuer, senior author of one of the papers, said the group very much thinks that adenovirus — primarily but not exclusively adenovirus 41 — is involved. “We feel very certain that the adenovirus is playing a role in some way,” Breuer, a clinical virologist at University College London and a consultant at Great Ormond Street Hospital for Children, told STAT in an interview.

Adeno-associated viruses are not typically looked for when clinicians are trying to figure out the cause of an illness, she said, because they haven’t been thought to be harmful. But her 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 the possible disease agents their specimens contained.

She warned, though, that it is still possible that AAV2 is a bystander, not part of the cause of these hepatitis cases.

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

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

Mario Koopmans, head of the department of viroscience at Erasmus Medical Center in Rotterdam, the Netherlands, said the theory is worthy of further investigation, but at this point is not conclusive. It “does suggest there is something to the combination of AAV2 and Adeno or possibly other viruses,” she said in an email.

The new studies still must go through peer review. But if they are correct, they will help to explain why some medical centers that treat children with liver ailments have seen what appear to be unusual numbers of cases of unexplained hepatitis starting last fall and through the spring.

More than 1,000 such cases from 35 countries have been reported to the World Health Organization. Of that total, 22 children have died and 46 have needed liver transplants. In the United States, 355 possible cases are under investigation, the Centers for Disease Control and Prevention says. As of late June, 20 of those children had required liver transplants and 11 had died.

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

“The current outbreak followed relaxation of restrictions due to the pandemic and represented one of many infections, including other enteric pathogens such as norovirus, that occurred in UK children following return to normal [social] mixing,” Breuer and her co-authors wrote.

Koopmans agreed. “The combination of two viruses and a genetic susceptibility factor does fit the hypothesis that the elevation in cases became visible due to the unusual occurrence of ‘common’ infections, as the patterns for several endemic viruses were disturbed by the COVID 19 control measures.”

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

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

But Rasmussen cautioned that there are more pieces of the puzzle to be found, including how this trio of factors would cause the damage that has been seen.

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

She also suggested it would be good if other groups could replicate the findings seen in these two groups of children from the U.K. “I would hope that all other investigators who have reported on these cases outside the U.K. are checking their sequence data for AAV2 sequences as well as doing some … genotyping.”

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

The efforts to figure out what was behind the cases — and whether indeed there was an outbreak underway — were complicated by the fact that data from the United States showed there had not been an increase in pediatric hepatitis of unknown origin, or liver transplants for pediatric hepatitis, or even of adenovirus 41 infections in the past year compared to prior to the pandemic. That does not mean there might not have been an increase in cases caused by this constellation of triggers, just that the overall number of cases of pediatric hepatitis for which a cause was not found had not changed.