Link Between Pediatric Hepatitis and
Adenovirus 41 Still Unclear

Lucy Hicks

July 13, 2022

While two new studies reiterate a possible relationship between adenovirus 41 and acute hepatitis of unknown cause in children, whether these infections are significant or merely bystanders remains unclear.

In both studies — one conducted in Alabama and the other conducted in the United Kingdom — researchers found that 90% of children with acute hepatitis of unknown cause tested positive for adenovirus 41. The virus subtype is not an uncommon infection, but it usually causes gastroenteritis in children.

"Across the world, adenovirus continues to be a common signal," in these pediatric hepatitis cases, said Helena Gutierrez, MD, the medical director of the Pediatric Liver Transplant Program at the University of Alabama at Birmingham, in an interview with Medscape Medical News. She led one of the studies. More data is necessary to understand what role this virus may play in these cases, she said.

In November, the Alabama Department of Public Health and the US Centers for Disease Control and Prevention (CDC) began investigating a cluster of severe pediatric hepatitis cases at the Children's of Alabama hospital in Birmingham. These children (in also tested positive for adenovirus. In April, the United Kingdom announced they were investigating similar cases, and the CDC expanded their search nationally. As of July 8, 1010 cases in 35 countries have been reported to the World Health Organization. There are 263 confirmed cases in the UK and 332 cases under investigation by the CDC in the US, according to the most recent counts.

The two studies, both published today in the New England Journal of Medicine, provide additional clinical data on a number of these mysterious hepatitis cases. Gutierrez's study looked at nine children admitted for hepatitis of unknown origin between October 1 and February 28. Patients had a median age of 2 years 11 months, two required liver transplants, and there were no deaths.

Eight out of nine patients (89%) tested positive for adenovirus, and all five of the samples that were of sufficient quality for gene sequencing tested positive for adenovirus 41. None of the six liver biopsies performed found signs of adenovirus infection, but the liver tissue samples of three patients tested positive for adenovirus via PCR.

The second study involved 44 children referred to a liver transplantation center in the United Kingdom between January 1 and April 11 of this year. The median age for patients was 4 years. Six children required liver transplants and there were no deaths. Of the 30 patients who underwent molecular adenovirus testing, 27 (90%) were positive for adenovirus 41. Liver samples of nine children (3 from biopsies and 6 from explanted livers) all tested negative for adenovirus antibodies.

In both studies, however, the median adenovirus viral load of patients needing a transplant was much higher than the viral loads in children who did not require liver transplants.

Although most of the clinical features and test results of these cases suggest that adenovirus may be involved, the negative results in histology are "intriguing," Chayarani Kelgeri, MD, a consultant pediatric hepatologist at the Birmingham Women's and Children's Hospital, UK, told Medscape in an email. She is the lead author of the UK study. "Whether this is because the liver injury we see is an aftermath of the viral infection, the mechanism of injury is immune mediated, and if other cofactors are involved is being explored," she added. "Further investigations being undertaken by UK Health Security Agency will add to our understanding of this illness."

Although there is a high adenovirus positivity rate amongst these cases, there is not enough evidence yet to say adenovirus 41 is a new cause of pediatric hepatitis in previously healthy children, said Saul Karpen, MD, PhD, the division chief of pediatric gastroenterology, hepatology, and nutrition at Emory University School of Medicine in Atlanta, Georgia. He wrote an editorial accompanying the two NEJM studies.

The CDC has not yet found an increase in pediatric hepatitis cases, according to a recent analysis, though the UK has found an uptick in cases this year, he told Medscape. Also, the cases highlighted in both articles showed no histological evidence of adenovirus in liver biopsies. "That's completely opposite of what we generally see in adenoviral hepatitis that can be quite severe," he said, adding that in general, there are detectable viral particles and antigens in affected livers.

"These two important reports indicate to those inside and outside the field of pediatric hepatology that registries and clinical studies of acute hepatitis in children are sorely needed," Karpen writes in the editorial; "It is likely that with greater attention to collecting data on cases and biospecimens from children with acute hepatitis, we will be able to determine whether this one virus, human adenovirus 41, is of relevance to this important and serious condition in children."

Gutierrez, Kelgeri, and Karpen report no relevant financial relationships.

New Eng J Med. Published online July 13, 2022.
US study, UK study, Editorial

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