For months, scientists around the world have been investigating cases of severe and unexplained hepatitis, or inflammation of the liver, 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 been elusive. A significant part of the cases of hepatitis in children have always been unexplained. There is still no consensus on whether these cases have become more common, and it is unclear 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, Alabama. Y another in Birmingham, England — have seen increases in the number of children with acute and 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 the children examined, 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 adenovirus could play a role,” 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 just in our cohort but across the world.”
But the evidence is far from definitive. And none of the studies found clear evidence that the virus was in the liver cells of any of the affected children, suggesting that if there was a link between adenovirus infections and hepatitis, it might not be a direct link.
“I don’t think it’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 articles. “I think that’s a main point.”
Not all medical centers have seen the same rise in cases, he noted, and a recent study by the Centers for Disease Control and Prevention found no evidence that unexplained hepatitis has become more common among American children overall.
The new cases may not necessarily represent “something new and scary,” he said. “On the other hand, you can’t ignore it.”
Hepatitis has a variety of causes, including certain medications and medical conditions, toxins, excessive alcohol use, and the hepatitis A through E viruses.
An inflammation of the liver usually caused by a virus, hepatitis carries with it a number of complicating factors, side effects and stigma.
Adenoviruses, a family of viruses that generally cause cold or flu-like symptoms, are not usually associated with liver inflammation in healthy children.
But doctors have detected adenovirus infections in many of the recent cases, including in a group of children in Alabama, the first group of cases reported in the United States.
One of the new documents provides more detail about hepatitis cases at the Children’s of Alabama hospital in Birmingham. During the five-month period from October 2021 to February 2022, the hospital admitted nine children with unexplained acute hepatitis, three times as many as 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 returned genomic sequences good enough to be analyzed further; all turned out to be adenovirus 41.
(During that same period, the hospital also admitted six children whose hepatitis had a known cause. Of the five tested for adenoviruses, all were negative, and a review of laboratory records suggested infections were not widespread in the population.) of hospital patients at the time.)
In Great Britain, 44 children with unexplained acute hepatitis were referred to Birmingham Women’s and Children’s Pediatric Liver Transplant Center between January 1 and April 11, 2022. Thirteen were admitted, plus one to five patients admitted to the same period of time in previous years.
Of the 30 children tested for adenovirus, 27 tested positive. The UK Health Security Agency later determined the virus to be adenovirus 41, said Dr. Chayarani Kelgeri, a 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 showed no evidence of viral proteins or particles in the liver cells themselves.
(PCR tests found adenovirus DNA in liver samples from several children, but these samples could have included blood mixed with liver tissue, making it difficult to determine whether the genetic material came from the liver or blood, the scientists said.)
“That leads us to wonder if the virus was there, but what we’re seeing in the liver samples is the sequelae of the viral injury,” Dr. Kelgeri said.
Perhaps, he said, an adenovirus infection triggers an abnormal immune response in some children, and it’s that immune response, not the virus, that damages the liver.
However, it is still unknown why some hospitals are seeing an increase in cases. If hepatitis has always been a rare result of adenovirus infections in children, cases could increase when the virus becomes more prevalent. The new cases of hepatitis in Britain coincided with “a report of increased adenoviruses” in the general population, Dr. Kelgeri noted.
It’s also possible that the virus has changed or that other factors, such as an earlier outbreak of Covid-19, have left some children more vulnerable to later adenovirus infection, the scientists said. (Of those tested, 28 per cent of British children tested positive for coronavirus, while 38 per cent tested positive for coronavirus antibodies.)
Dr. Karpen said 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 am very happy that registries are being created to find out if there really is a new virus in the city that needs attention,” said Dr. Karpen. “We really need to continue to collect information and keep our eyes open.”