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Scientists are edging closer to unraveling the mystery of unexplained hepatitis cases in children. Annie Otzen/Getty Image
  • Two separate pre-print studies offer clues to explain the mystery behind what is causing unexplained acute hepatitis in children.
  • Scientists have detected several potential culprits in affected children: a benign virus, two adenoviruses, and a small amount of herpes virus, as well as a specific gene mutation.
  • The authors of the studies are now looking to researchers in other geographic regions to confirm their findings.

Since January 2022, physicians have been treating unexplained cases of acute hepatitis in young children, some of whom have required liver transplants and some of whom have died. With the first cases diagnosed in Scotland and then spreading across the globe with over 1,000 cases, the cause of the outbreak has remained unclear.

In any aspect of life, problems with a single cause are typically simpler to work out. Solutions to problems with multiple possible factors can be maddeningly difficult to unravel, as has been the case with these hepatitis cases.

A pair of new independent but overlapping studies suggest that the unexplained cases of hepatitis in children are likely the result of one — or two — interacting viruses and perhaps a gene mutation.

One of the studies was conducted at the University of Glasgow in Scotland, and the other at UCL Great Ormond Street Institute of Child Health in London, both in the U.K.

The studies detected high levels of genetic material from Adeno-associated virus 2, or AAV2, in nearly all affected children, although not in healthy children used as controls. AAV2 is very common, infecting nearly everyone in childhood, and may remain in the body at low levels indefinitely.

AAV2 is considered harmless and is not known to cause illness, adding to the mystery.

Intriguingly, since AAV2 can only replicate in the presence of other adenoviruses or herpes viruses, its presence may suggest that one of them is involved in these unexplained cases of hepatitis.

The Scottish researchers did find traces of likely adenoviruses HAdV (species C and F) and human herpes virus 6B (HHV6B). Researchers found HAdV C and F in six out of nine affected children and HHV6B in three out of nine.

In addition, eight out of nine of the children with acute hepatitis in the Scottish study shared a gene mutation, HLA-DRB1*04:01. The mutation is not very common, present in only about 15.6% of Scottish blood donors.

Dr. Paul Spearman, director of the Division of Infectious Diseases at Cincinnati Children’s Hospital, who was not involved in either study, told Medical News Today said the findings were intriguing but needed to be explored further.

“These are intriguing studies that raise the possibility of AAV2, in combination with adenovirus, contributing to the hepatitis cases seen in children. The numbers are small, and the associations made can’t be said to be definitive. This will require larger studies.”
— Dr. Paul Spearman

“However, now the larger studies can also look for AAV2, and try to strengthen this finding. So, the importance here is that this is a potential clue to the cause, and now we have to take this observation and apply it more broadly to see if the link holds,” Dr. Spearman added.

Professor Emma Thompson, corresponding author of the Scottish study, told MNT “The first step is for others to test for AAV2 and the HLA association in their cohorts around the world.

” We already have two independent studies that showed the same thing — but it’ll be important to see if this is also the case in other countries,” she said.

Dr. Spearman noted that physicians and researchers shouldn’t have much trouble testing for the gene mutation: “This is a very simple test. Most hospitals or reference laboratories can perform this test.”

“Secondly,” said Prof. Thompson, “we need some more mechanistic work. One such research avenue is to look at IgM antibody responses (which rise in primary infection) to see if the children were infected recently.” IgM immunoglobulins are produced in response to a foreign pathogen by the body’s immune system.

Prof. Thompson also recommended exploring “the immune response — antibody and T cell — to proteins from AAV2 [and] HAdV.” She also mentioned HHV6, herpes, as a possible candidate, though she suspects it is much less likely to be involved.

Finally, “we need to investigate if the HLA-DRB1*:0401 is involved in presenting peptides that come from AAV2 or HAdV viruses to T cells. All of these studies are being planned at the moment,” said Prof. Thompson.

The UCL study found high levels of AAV2 in blood and in the tissue of livers removed from children with unexplained hepatitis who were known to have been infected during a recent AdV-F41 outbreak.

However, they write, “We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of [H]AdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus.”

Professor Judith Breuer, corresponding author of the UCL study, tells New Scientist that these findings suggest that there is “an indirect viral mechanism.”

Prof. Thompson said there were two possibilities and further explained to MNT:

“It could be that the methods we are using are not sensitive enough to detect protein, so more antibody work is needed to be sure about that. If there truly is a lack of protein, then I think that the mechanism would be most likely to be immune-directed, possibly for example as a cross-reactive response from antibodies or T cells to liver cells.”

“While the genetic footprint of AAV2 is still very apparent,” added Prof. Thompson, “the immune response has already cleared the protein by the time the children come to hospital. We need to do a lot more to look into these mechanistic questions.”

Prof. Thompson hypothesized why it might be that these unexplained cases of hepatitis may only be happening to children:

“I suspect that this might be a ‘multi-hit’ phenomenon, that the children may have the underlying susceptibility and have been exposed to both HAdV and AAV2 for the first time, while most adults will already have had exposure to these viruses (possibly one at a time).”

“You can speculate,” suggested Dr. Spearman, “that if AAV2 is contributing to the liver inflammation, it might only do this during initial infection in children together with adenovirus and not with reactivation in older individuals.”

“However, we need to do a lot more work to investigate that,” said Prof. Thompson. “This would mean that we may have missed occasional cases in the past in children. We also need to know what the seasonal trends of AAV2 exposure look like.”

“Many, many questions still to answer!” she concluded.