For months, scientists around the world have been investigating cases of severe, unexplained hepatitis, or liver inflammation, in previously healthy children. At least 920 probable cases have been detected in 33 countries since October, according to the World Health Organization. About 5 percent have required liver transplants, and 18 deaths have been reported.
So far, explanations have remained elusive. A significant share of hepatitis cases in children have always been unexplained. There is still no consensus on whether such cases have become more common, and it is not clear whether the recently reported cases, which remain rare, are part of a new medical phenomenon or share an underlying cause.
But more detailed case investigations are beginning to provide clues.
Two new studies, published in the New England Journal of Medicine on Wednesday, report that two medical centers — one in Birmingham, Ala. and another in Birmingham, England — have seen increases in the number of children with acute, unexplained hepatitis in recent months.
The research also presents more circumstantial evidence that adenovirus 41, which often causes gastrointestinal symptoms, may be a contributing factor. In both studies, adenovirus infections were detected in about 90 percent of children tested, and children who developed acute liver failure or required transplants had higher average levels of the virus in their blood than those with milder cases.
“I think that adenovirus could be a player,” said Dr. Helena Gutierrez Sanchez, medical director of the pediatric liver transplant program at the University of Alabama at Birmingham and an author of one of the new papers. “It seems to be that common signal, not only in our cohort but across the globe.”
But the evidence is far from definitive. And neither study found clear evidence that the virus was in the liver cells of any of the affected children, which suggested that if there were a link between adenovirus infections and hepatitis, it might not be a straightforward one.
“I don’t think that’s a subtle point,” said Dr. Saul Karpen, a pediatric hepatologist at Emory University and Children’s Healthcare of Atlanta who wrote an editorial that accompanied the two new papers. “I think that’s a main point.”
Not all medical centers have seen the same increase in cases, he noted, and a recent study from the Centers for Disease Control and Prevention did not find evidence that unexplained hepatitis had become more common among American children overall.
The new cases may not necessarily represent “something new and frightening,” he said. “On the other side, you can’t ignore it.”
Hepatitis has a variety of causes, including certain medications and medical conditions, toxins, heavy alcohol use and the hepatitis A through E viruses.
An inflammation of the liver generally caused by a virus, hepatitis carries a host of complicating factors, side effects and stigma.
Adenoviruses, a family of viruses that usually cause cold- or flulike symptoms, are not typically associated with liver inflammation in otherwise healthy children.
But clinicians have detected adenovirus infections in many of the recent cases, including in a group of children in Alabama, the first cluster of cases reported in the United States.
One of the new papers provides more details about hepatitis cases at the Children’s of Alabama hospital in Birmingham. During the five-month period from October 2021 through February 2022, the hospital admitted nine children with acute, unexplained hepatitis, three times as many as were admitted in the entire previous year. “At least in our center, we had a spike,” Dr. Gutierrez said.
Blood samples from eight of those nine children tested positive for an adenovirus. Viral samples from five children yielded genomic sequences good enough to be analyzed further; all turned out to be adenovirus 41.
(During that same time period, the hospital also admitted six children whose hepatitis had a known cause. Of the five tested for adenovirus, all were negative, and a review of lab records suggested that the infections were not widespread in the hospital’s overall patient population at the time.)
In Britain, 44 children with acute, unexplained hepatitis were referred to the pediatric liver transplantation center at Birmingham Women’s and Children’s between Jan. 1 and April 11 in 2022. Thirteen were admitted, more than the one to five patients admitted in the same time frame in previous years.
Of the 30 children tested for adenovirus, 27 were positive. The U.K. Health Security Agency later determined that the virus was adenovirus 41, said Dr. Chayarani Kelgeri, consultant pediatric hepatologist at Birmingham Women’s and Children’s and an author of the study.
The picture became more complicated when the scientists analyzed liver samples from a subset of affected children. Laboratory tests turned up no evidence of viral proteins or particles in the liver cells themselves.
(P.C.R. testing did find adenovirus DNA in liver samples from several children, but these samples might have included blood mixed with liver tissue, making it difficult to determine whether the genetic material came from the liver or the blood, the scientists said.)
“That leads us to question whether virus was there but what we are seeing in the liver samples is an aftermath of the viral injury,” Dr. Kelgeri said.
Perhaps, she said, an adenovirus infection triggers an abnormal immune response in some children, and it is that immune response, rather than the virus, that damages the liver.
Why some hospitals are seeing a rise in cases remains unknown, though. If hepatitis has always been a rare outcome of adenovirus infections in children, cases could rise when the virus becomes more prevalent. The new hepatitis cases in Britain did coincide with “a report of increased adenovirus” in the broader population, Dr. Kelgeri noted.
It is also possible that the virus has changed or that other factors — such as a previous bout of Covid-19 — might have left some children more vulnerable to a subsequent adenovirus infection, scientists said. (Of those tested, 28 percent of the British children tested positive for the coronavirus, while 38 percent tested positive for coronavirus antibodies.)
Dr. Karpen said that he was not yet convinced that there was a link between adenovirus infection and pediatric hepatitis — or that the incidence of either was increasing overall. Regardless, more systematic data collection and analysis is needed, he said.
“I’m very happy that registries are being created so that we will know whether or not there truly is a new virus in town that needs attention,” Dr. Karpen said. “We really need to just continue to collect information and keep our eyes open.”