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Studies probe link between adenovirus and childhood hepatitis cases

For months, scientists around the world have investigated cases of severe, 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% required liver transplantation and 18 deaths were reported.

So far, explanations have remained elusive. A significant proportion of childhood hepatitis cases have always been unexplained. There is still no consensus on whether these cases have become more frequent, and it is unclear whether the recently reported cases, which remain rare, are part of a new medical phenomenon or share a underlying cause.

But more detailed investigations of the cases 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 the other in Birmingham, England – have seen an increase in the number of children with unexplained acute hepatitis in recent years. month.

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 approximately 90% of children tested, and children who developed acute liver failure or required transplants had higher mean levels of virus in their blood than those with milder cases.

“I think 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 author of one of the new papers. “That seems to be that common signal, not just in our cohort but around the world.”

But the evidence is far from definitive. And no study has 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 could not be straightforward.

“I don’t think it’s a subtle point,” said Dr. Saul Karpen, a pediatric hepatologist at Emory University and Children’s Healthcare in Atlanta, who wrote an editorial accompanying the two new articles. “I think that’s a key point.”

Not all medical centers have seen 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 people. American children in general.

The new cases don’t necessarily represent “something new and scary”, he said. “On the other side, you can’t ignore it.”

Hepatitis has a variety of causes, including certain medications and medical conditions, toxins, excessive alcohol consumption, and hepatitis A through E viruses.

Adenoviruses, a family of viruses that typically cause cold or flu symptoms, are not usually associated with liver inflammation in otherwise healthy children.

But clinicians have detected adenovirus infections in many recent cases, including in a cluster of children in Alabama, the first cluster of cases reported in the United States.

One of the new articles provides more details about the hepatitis cases at Alabama Children’s Hospital in Birmingham. In the five-month period from October 2021 to February 2022, the hospital admitted nine children with unexplained acute hepatitis, three times more than those admitted in the entire previous year. “At least in our center we had a spike,” Dr. Gutierrez said.

Blood samples from eight of these nine children tested positive for adenovirus. Viral samples from five children yielded genomic sequences good enough for further analysis; all turned out to be adenovirus 41.

(During this same 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 laboratory records suggested that the infections were not prevalent among the general patient population of the hospital at the time.)

In Britain, 44 children with unexplained acute hepatitis were referred to the Birmingham Women’s and Children’s Pediatric Liver Transplant Center between January 1 and April 11, 2022. Thirteen were admitted, more than one in five patients admitted in the same period of time. in previous years.

Of the 30 children tested for adenovirus, 27 were positive. The UK Health Safety Agency later determined the virus to be adenovirus 41, said Dr Chayarani Kelgeri, consultant pediatric hepatologist at Birmingham Women’s and Children’s and study author.

The picture became more complicated when scientists analyzed liver samples from a subset of affected children. Laboratory tests revealed no evidence of proteins or virus particles in the liver cells themselves.

(PCR tests have found adenovirus DNA in liver samples from several children, but these samples may 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.)

“This makes us wonder if the virus was there, but what we see in liver samples is a consequence of viral injury,” Dr Kelgeri said.

Perhaps, she said, an adenovirus infection triggers an abnormal immune response in some children, and it is this immune response, rather than the virus, that damages the liver.

Why some hospitals are seeing an increase in cases, however, remains unknown. While hepatitis has always been a rare consequence of adenovirus infections in children, cases could increase as the virus becomes more prevalent. The new cases of hepatitis in Britain coincided with “an increased adenovirus report” in the general population, Dr Kelgeri noted.

It’s also possible that the virus has changed or other factors – such as a previous episode of Covid-19 – have left some children more vulnerable to later infection with an adenovirus, scientists have said. (Of those tested, 28% of UK children tested positive for coronavirus, while 38% 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. Either way, more systematic data collection and analysis is needed, he said.

“I’m very happy that registries are being created so that we know whether or not there really is a new virus in town that needs attention,” Dr Karpen said. “We really need to keep collecting information and keep our eyes peeled.”