Clinical Context

Adenoviruses are double-stranded DNA viruses that can promote a variety of different symptoms when they infect humans. Gutierrez Sanchez and colleagues, who reported on a case series of ill children admitted to Children's of Alabama hospital between October 1, 2021 and February 28, 2022, noted that liver involvement among children infected with adenovirus is usually limited to acute subclinical hepatitis. Children with a history of immunocompromise may suffer fulminant liver failure associated with adenovirus infection; however, there has been a highly disturbing trend of previously healthy children with severe liver injury, and adenovirus may be the cause. They reported on a case series of 15 children with acute hepatitis admitted to their center and published their findings in the New England Journal of Medicine on July 13.^[1]

Nine of these patients had no cause of hepatitis diagnosed after a thorough workup; 89% of these children tested positive for adenovirus on PCR testing, and all 9 tested negative for infection with SARS-CoV-2. Higher viral loads of adenovirus were associated with a worse prognosis.

The median age of these 9 patients was 2 years 11 months. Six children recovered with supportive therapy alone, but 3 children developed acute liver failure: 2 of these children received liver transplantation.

Another study in the July 13 issue of theNew England Journal of Medicine^[2] describes a larger cohort of children with acute hepatitis related to adenovirus in the United Kingdom. The results of this study are summarized in "Study Highlights."

Study Synopsis and Perspective

Although 2 new studies^[1,2] 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^[1] and the other conducted in the United Kingdom^[2] -- 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 Sanchez, 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.^[1] More data are necessary to understand what role this virus may play in these cases, she said.

In November, the Alabama Department of Public Health and the 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.^[1] These children also tested positive for adenovirus. In April, the United Kingdom announced they were investigating similar cases,^[2] and the CDC expanded their search nationally.^[1] As of July 8, a total of 1010 probable cases in 35 countries have been reported to the World Health Organization.^[3] There are 26ref3 confirmed cases in the United Kingdom^[4] and 355 cases under investigation by the CDC in the United States,^[5] according to the most recent counts.

The two studies, both published July 13 in the New England Journal of Medicine,^[1,2]  provide additional clinical data on some of these mysterious hepatitis cases. Gutierrez Sanchez's study^[1] looked at 9 children admitted for hepatitis of unknown origin. Patients had a median age of 2 years 11 months; 2 required liver transplants; and there were no deaths.

Of 9 patients, 8 (89%) tested positive for adenovirus, and all 5 of the samples that were of sufficient quality for gene sequencing tested positive for adenovirus 41. None of the 6 liver biopsies performed found signs of adenovirus infection, but the liver tissue samples of 3 patients tested positive for adenovirus via PCR.

The second study^[2] 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 9 children (3 from biopsies and 6 from explanted livers) all tested negative for adenovirus antibodies.

In both studies,^[1,2] 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, United Kingdom, told Medscape in an email. She is the lead author of the UK study.^[2]

"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^[6] accompanying the two NEJM studies.

The CDC has not yet found an increase in pediatric hepatitis cases, according to a recent analysis,^[7] although the United Kingdom 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.^[1,2]

"That's completely opposite of what we generally see in adenoviral hepatitis that can be quite severe," he said and added 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 wrote in the editorial.^[6] "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 Sanchez, Kelgeri, and Karpen reported no relevant financial relationships.

Clinical Implications

• In one case series of 9 children with acute hepatitis without an obvious cause, 89% tested positive for adenovirus on PCR testing. All 9 tested negative for infection with SARS-CoV-2. Higher viral loads of adenovirus were associated with a worse prognosis. Six children with hepatitis recovered with supportive therapy alone, but 3 children developed acute liver failure: 2 of these children received liver transplantation.
• In the other case series of 44 children with acute hepatitis related to infection with adenovirus, jaundice was the most common presenting symptom.
• Implications for the healthcare team: The healthcare team should be aware of the risk of acute hepatitis in children, possibly associated with adenovirus infection. Children presenting with prodromal symptoms followed by jaundice should be promptly evaluated.

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