Scientists around the world have been studying cases of severe and unexplained hepatitis (inflammation of the liver) in previously healthy children for months. At least 920 probable cases have been detected in 33 countries since October, according to the WHO (World Health Organization). Among these cases, 5% required liver transplants and 18 deaths were reported.
The cases are still unexplained. An important portion of hepatitis cases in children has always been unexplained. There is still no consensus on whether these cases are becoming more common. Nor is it clear whether the newly reported cases, which are still rare, are part of a new medical phenomenon or if they share a common underlying cause.
But more detailed investigations are starting to point to clues.
Two new studies published Wednesday in the New England Journal of Medicine reveal that two medical centers — one in Birmingham, Alabama, and the other in Birmingham, England — have seen an increase in the number of children with acute and unexplained hepatitis.
The research also provided more circumstantial evidence that a contributing factor to hepatitis cases may be adenovirus 41, which often causes gastrointestinal symptoms. In both studies, adenovirus infections — a common pathogen that causes colds and flu — were detected in 90% of the children tested. Children who developed acute liver failure or needed a transplant had higher average levels of the virus in their blood than children with milder hepatitis.
“I think adenovirus may be a factor here,” said Helena Gutierrez Sanchez, medical director of the pediatric liver transplant program at the University of Alabama at Birmingham and author of one of the new papers. “It appears that this is a common sign, not just in our cohort. [grupo de participantes analisados no estudo]but all over the world.”
But the evidence is far from definitive. Neither of the two studies found clear evidence that the virus was present in the liver cells of any of the affected children. This suggests that if there is a link between adenovirus infections and hepatitis, it may not be a direct one.
“I don’t think this is a subtle point,” commented pediatric hepatologist Saul Karpen of Emory University and Children’s Healthcare in Atlanta, who wrote an editorial on the two new studies. “I think it’s a main point.”
Karpen pointed out that not all medical centers have seen the same increase in the number of cases. Additionally, a recent CDC (Centers for Disease Control and Prevention) study found no evidence that unexplained hepatitis had become more common among American children overall.
The new cases may not necessarily represent “something new and scary,” he noted. “On the other hand, we can’t ignore them.”
Hepatitis can have a number of causes, including certain medications and medical conditions, toxins, high alcohol consumption, and hepatitis A to E viruses.
Adenoviruses, a family of viruses that commonly cause cold or flu symptoms, are not typically 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 studies sheds more light on hepatitis cases at the Children’s Hospital of Alabama in Birmingham. Over a five-month period between October 2021 and February 2022, the hospital took in nine children with acute, unexplained hepatitis — three times as many as had been admitted in the entire previous year. “In our center, at least, we’ve had a sharp increase,” Gutierrez said.
Blood samples from eight of those nine children tested positive for the adenovirus. Viral samples from five children produced genomic sequences good enough to be analyzed extensively. All turned out to be adenovirus 41.
During that same period, the hospital also took in six children whose hepatitis had a known cause. Of the five tested for adenovirus, all were negative. A review of laboratory records suggested that the infections were not widespread in the hospital’s general patient population at the time.
In the UK, 44 children with acute, unexplained hepatitis were referred to the Pediatric Liver Transplant Center at Birmingham Women’s and Children’s Hospital between 1 January and 11 April 2022. 13 of them were hospitalized, more than 1 to 5 patients hospitalized in the same period in previous years.
Of the 30 children tested for adenovirus, 27 tested positive. The British Health Safety Agency later determined that the virus was adenovirus 41, said pediatric hepatologist Chayarani Kelgeri, one of the study’s authors.
The picture got more complicated when scientists analyzed liver samples from a subset of affected children. Laboratory tests have produced no evidence of proteins or viral particles in the liver cells themselves.
PCR tests found adenovirus DNA in liver samples from several children, but those samples may have included blood mixed with liver tissue, so it would be difficult to determine whether the genetic material came from the liver or blood, the scientists said.
“This leads us to question whether the virus was present, but what we were seeing in the liver samples would be a consequence of the viral injury,” Kelgeri said.
For her, it is possible that an adenovirus infection triggers an abnormal immune response in some children and that it is this response, and not the virus, that damages the liver.
But it remains to be seen why some hospitals are seeing an increase in cases. If hepatitis has always been a rare result of adenovirus infections in children, cases may increase as the virus becomes more prevalent. Kelgeri noted that, in fact, the new cases of hepatitis in the UK coincided with “a report of an increase in adenovirus” in the larger population.
Scientists say it is also possible that the virus has undergone changes or that other factors — such as a previous Covid infection — have left some children more vulnerable to a subsequent adenovirus infection. Among children tested, 28% of British children tested positive for the coronavirus, while 38% had antibodies to the coronavirus.
Karpen said he is still not convinced that there is a link between adenovirus infection and pediatric hepatitis, nor that the incidence of either is increasing altogether. Even so, he pointed out, a more systematic work of data collection and analysis is needed.
“I’m pleased that records are being created so that we know if there is indeed a new virus on the block that requires our attention,” Karpen said. “What we really need to do is just continue to gather information and be on the lookout.”
Translation by Clara Allain
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