Unexplained Acute Hepatitis in Children: More Evidence for Adenovirus 41

Two case series of children with unexplained acute hepatitis from the U.S. and U.K. pointed to human adenovirus viremia in most and strengthened the case for adenovirus 41 as a potential cause.

Among nine such children seen in Alabama from October 2021 through February 2022, eight tested positive for human adenovirus, reported L. Helena Gutierrez Sanchez, MD, of the University of Alabama at Birmingham, and colleagues.

While immunohistochemistry or electron microscopy didn't turn up evidence of human adenovirus, PCR testing of liver tissue came out positive for it in three kids (50% of those tested).

Among 44 children with acute hepatitis of unknown cause at one of the three pediatric liver-transplant centers in the U.K. from January 1 to April 11, 2022, 27 of the 30 who had molecular testing for human adenovirus were positive, said Chayarani Kelgeri, MD, of Birmingham Women's and Children's NHS Foundation Trust in England, and colleagues.

Both case series were published in the New England Journal of Medicine.

The findings fit with what was seen in a U.K. Health Security Agency technical briefing report, which showed that 116 of the 179 cases who underwent molecular testing were positive for human adenovirus, with the subtype reported to be 41F.

While human adenovirus 41 has largely been linked to acute gastroenteritis, 14% of the children in the U.K. series and two of the nine in the U.S. series required liver transplantation.

"With reports like these from around the globe, is there sufficient evidence that human adenovirus 41 is a new cause of pediatric liver failure? There is not yet completely convincing evidence of a causal link, since at least in the United States there has not been an increase in reported cases of adenoviral hepatitis," wrote Saul J. Karpen, MD, PhD, of Emory University School of Medicine in Atlanta and Children's Healthcare of Atlanta, in an accompanying editorial.

The researchers in both case series also acknowledged that the retrospective data could not prove causation. And, as Karpen pointed out, several of the patients received antiviral cidofovir treatment without a clear impact on outcomes.

"Moreover, none of the histologic evaluations have revealed evidence of hepatocellular adenoviral infection, as was expected by those of us who have cared for mainly immunocompromised patients with florid adenoviral hepatitis," he added.

"Without evidence of adenovirus-mediated tissue damage, these studies are not yet sufficient to declare human adenovirus 41 a firm cause of acute hepatitis that can lead to liver failure," Karpen continued. "Alternatives to consider include human adenovirus 41 potentially serving as an immunologic activator or even as an innocent, readily detected bystander. Crucial unknowns must be resolved before etiologic guilt can be assigned or practice guidance regarding the initiation of therapy can be provided."

The "sorely needed" registries and clinical studies of acute hepatitis in children to answer such questions are being developed in Europe and in North America, he noted.

The two series used slightly different criteria for cases. In the U.K. series, criteria were based on the confirmed case definition of the U.K. Health Security Agency: acute hepatitis in a child ages 10 years or younger (median 4, range 1-7 in the series) that was not hepatitis A through E and with no metabolic, inherited or genetic, congenital, or mechanical cause and with a serum aminotransferase level over 500 IU/L. Most of the patients presented with jaundice (93%) and gastrointestinal symptoms (54% vomiting and 32% with diarrhea).

In the U.S. series, the aminotransferase threshold was over 250 U/L for alanine aminotransferase and over 440 U/L for aspartate aminotransferase and children were included up to age 18 years, although the oldest child in the series was under 7 years (median 2 years, 11 months) for the eight patients with hepatitis of unknown cause treated at the single center and one additional patient referred to it for follow-up for the same condition.