Last year, reports of severe, unexplained hepatitis in previously healthy children puzzled health experts around the world.
Now, a small new study of American children adds to the evidence that the cases, which remained extremely rare, may have been caused by a simultaneous infection with multiple common viruses, including one known as adeno-associated virus type 2, or AAV2.
AAV2 is not typically associated with disease, and it requires a second “helper” virus in order to replicate. Many of the children with unexplained hepatitis, or liver inflammation, were infected with multiple helper viruses, the researchers found.
Although the idea remains speculative, the timing of the outbreak may have been related to the loosening of pandemic precautions, leaving large numbers of young children exposed to common viruses they had not previously encountered.
“It may have resulted in a population that was highly vulnerable to getting infected with multiple viral infections,” said Dr. Charles Chiu, an infectious disease specialist and microbiologist at the University of California, San Francisco, and an author of the new study.
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The research appeared Thursday in the journal Nature, alongside two British studies that also implicated AAV2 in the hepatitis cases. Preliminary versions of the British studies were posted online last summer.
The consistent findings are “quite striking,” said Dr. Frank Tacke, head of the gastroenterology and hepatology department at the Charité University Medical Center in Berlin, who was not involved in the research but wrote an accompanying commentary. “The fact that three independent groups found this from different areas of the world actually makes it really convincing.”
Still, the findings are not definitive, and many uncertainties remain, including how these infections might trigger hepatitis and whether AAV2 plays a causal role or is “just a bystander,” Dr. Tacke said. (There has also been some debate about whether the cases truly became more common last year or whether they were part of a previously unrecognized phenomenon.)
The cases date back to the fall of 2021 but seemed to peak last spring and summer before tapering off, experts said. By last July, more than 1,000 probable cases had been reported in 35 countries, including the United States, according to the World Health Organization. Roughly 5 percent of children required liver transplants, and 2 percent died.
In several early studies, scientists found that many of the affected children were infected with adenoviruses, particularly adenovirus 41, which typically causes gastrointestinal symptoms. Adenoviruses are not typically known to cause hepatitis in otherwise healthy children, but they are common helper viruses for AAV2.
The new study was a collaboration among academic researchers, state health departments and the Centers for Disease Control and Prevention, among other institutions. The researchers studied biological samples from 16 American children, from six states, with unexplained hepatitis. All had previously tested positive for an adenovirus. They also studied samples from 113 control children, a group that included healthy children, children with gastroenteritis and children with hepatitis from a known cause.
Blood samples were available from 14 of the children with unexplained hepatitis. The researchers found AAV2 in 13 of those children, or 93 percent of them, compared with 3.5 percent of control children. Among the 30 children who had hepatitis linked to a known cause, none tested positive for AAV2.
Most of the children with unexplained hepatitis also tested positive for at least one herpes virus, which means that many were infected by at least three viruses: AAV2, an adenovirus and a herpes virus.
In the British studies, which were also small, scientists found AAV2 in the blood and livers of affected children. Many were also infected with an adenovirus or herpes virus. In one study, 25 of 27 affected children shared an immune-related genetic variant that is relatively uncommon in the general population. The finding suggests that this variant might predispose some children to hepatitis when they are infected by AAV2 and one or more helper viruses.
“It may turn out that in rare cases, you have kind of a perfect storm of events, where there’s a subset of children who were uniquely susceptible,” Dr. Chiu said.
More research is necessary to determine whether one or more of these viruses were injuring the liver directly, he said.
An alternative explanation is that, in a small subset of children, infection with multiple viruses triggers an overly strong immune response, which damages the liver.
Nailing down the mechanism would have important implications for treatment, Dr. Tacke added. If the viruses are damaging the liver, then antivirals might be the best course of treatment; if an immune overreaction is to blame, then suppressing the immune response with steroids might be a better choice, he said.