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 required liver transplants, and 18 deaths were reported.
So far there have been no explanations. A significant proportion of hepatitis cases in children has 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 that remain rare are part of a new medical phenomenon or have an underlying cause.
But more detailed case studies are beginning to provide clues.
Two new studies published Wednesday in the New England Journal of Medicine report that two medical centers — one in Birmingham, Alabama and another in Birmingham, England — have seen an increase in the number of children with acute, unexplained cervical cancer in recent months have recorded hepatitis.
The research also provides further circumstantial evidence that adenovirus 41, which commonly causes gastrointestinal symptoms, may be a contributing factor. In both studies, adenovirus infections were found in about 90 percent of the children tested, and children who developed acute liver failure or needed transplants had higher average levels of the virus in their blood than those with milder cases.
“I think the 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 author of one of the new papers. “It seems to be this common signal, not just in our cohort but around the world.”
But the evidence is far from conclusive. And none of the studies found clear evidence that the virus was in the liver cells of any of the affected children, suggesting that a link between adenovirus infections and hepatitis may not be straightforward.
“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 to accompany the two new articles. “I think that’s a main point.”
Not all medical centers saw the same increase in cases, he noted, and a recent study by the Centers for Disease Control and Prevention 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 said. “On the other hand, you can’t ignore it.”
Hepatitis has a variety of causes, including certain medications and medical conditions, toxins, heavy drinking, and the hepatitis A through E viruses.
Hepatitis is an inflammation of the liver, generally caused by a virus, and carries with it a variety of complicating factors, side effects, and stigma.
Adenoviruses, a family of viruses that usually cause cold- or flu-like symptoms, are not usually associated with liver inflammation in otherwise healthy children.
But clinicians have detected adenovirus infections in many of the recent cases, including a group of children in Alabama, the first group of cases reported in the United States.
One of the new releases provides more details on hepatitis cases at the Children’s of Alabama Hospital in Birmingham. In the five months from October 2021 to February 2022, the hospital admitted nine children with acute unexplained hepatitis, three times the number for all of the previous year. “At least at our center, we’ve had an increase,” said Dr. approval rec.
Blood samples from eight of these 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 the same period, the hospital also admitted six children whose hepatitis had a known cause. Of the five who tested for adenovirus, all tested negative, and a review of laboratory records indicated that the infections were not widespread throughout the hospital’s patient population were then.)
In the UK, between 1 January and 11 April 2022, 44 children with acute unexplained hepatitis were referred to the Birmingham Women’s and Children’s Pediatric Liver Transplant Center. Thirteen were enrolled, more than one to five patients enrolled in the same period in previous years.
Of the 30 children tested for adenovirus, 27 were positive. The UK Health Security Agency later found the virus to be adenovirus 41, said Dr. Chayarani Kelgeri, Consultant Pediatric Hepatologist at Birmingham Women’s and Children’s and author of the study.
The picture became more complicated when the scientists analyzed liver samples from a subset of affected children. Laboratory tests found no evidence of viral proteins or particles in the liver cells themselves.
(PCR tests found adenovirus DNA in liver samples from several children, but those samples may have contained 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 wonder if virus was present, but what we’re seeing in the liver samples is a consequence of viral injury,” said Dr. Kelgeri.
Perhaps, she said, adenovirus infection triggers an abnormal immune response in some children, and it is that immune response rather than the virus that damages the liver.
But why some hospitals are seeing a spike in cases remains unknown. If hepatitis has always been a rare consequence of adenovirus infection in children, cases could increase as the virus becomes more common. The new hepatitis cases in the UK coincided with “a report of increased adenovirus” in the wider population, noted Dr. Kelgeri firmly.
It’s also possible that the virus has changed, or that other factors – such as a previous bout of Covid-19 – may have made some children more susceptible to subsequent adenovirus infection, scientists said. (Of those tested, 28 per cent of UK children tested positive for the coronavirus, while 38 per cent tested positive for coronavirus antibodies.)
dr Karpen said he’s not yet convinced there’s a link between adenovirus infection and pediatric hepatitis — or that the incidence of both is increasing overall. Regardless, more systematic data collection and analysis is needed, he said.
“I am very pleased that registers are being drawn up so that we know if there really is a new virus in the city that needs attention,” said Dr. carp. “We just have to keep gathering information and keeping our eyes peeled.”