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Genotyping results from blood samples of U.S. children with severe acute support prior research suggesting that adeno-associated virus 2 (AAV2) along with a "helper" virus may be to blame for last year's global outbreak.

In 13 of 14 mystery hepatitis cases (93%), blood samples turned up positive for AAV2 -- a virus not previously recognized as pathogenic, and which relies on a helper virus to replicate -- as compared with 4 of 113 control samples (3.5%; P<0.001), reported Charles Chiu, MD, PhD, of the University of California San Francisco, and colleagues.

All 14 children had previously tested positive for adenovirus, with type 41 being most common, in 11 cases (79%), while other co-infections included Epstein-Barr virus, herpesvirus 6, and enterovirus A71, in 12 cases (85.7%).

Adenovirus type 41, an early potential culprit in the outbreak, was detected in just 8% of control samples, which included children hospitalized with hepatitis of defined etiology, while other co-infecting viruses were also rare among controls.

"Taken together, these findings show a significant association between co-infection by AAV2 and one or more hepatotropic viral pathogens and the clinical manifestations of severe acute hepatitis, although a direct causal link has yet to be confirmed," the researchers wrote in .

They suggested that the situation may be analogous to the sudden liver failure that can occur with overlapping chronic hepatitis B and hepatitis D virus infections.

In a , Chiu said the researchers were "surprised" that the infections detected were not caused by an unusual, emerging virus, but rather common childhood viral pathogens. Infections from adeno-associated viruses usually peak in kids ages 1 to 5 years, according to the release -- the affected children in the current study had a median age of 3 years.

"That's what led us to speculate that the timing of the outbreak was probably related to the really unusual situations we were going through with COVID-19-related school and daycare closures and social restrictions," Chiu said. "It may have been an unintended consequence of what we have experienced during the last 2-to-3 years of the pandemic."

Since 2022, more than 1,000 cases of acute pediatric hepatitis of unknown cause across 35 countries have been reported to the World Health Organization. In the U.S., the 391 cases under investigation across 46 states and jurisdictions, including at least .

The new findings support two prior studies from the U.K. -- initially published last year as preprints and now published in Nature along with Chiu's study -- that also linked AAV2 to the outbreak.

"All three studies make the same observation of AAV2 in children with unexplained acute hepatitis. That the studies took place on two continents adds to their value," said Frank Tacke, MD, PhD, of Charité University Medical Center Berlin, in an .

"Going forward, in-depth immunological analyses will be eagerly awaited. In addition, analysis of any direct toxic effects of AAV2 on liver cells -- using 3D cultures called liver organoids, for instance -- will be needed to understand how AAV2 infection (with or without helper viruses) might affect hepatocyte metabolism and viability," he continued. "This distinction between immune-mediated and hepatotoxic effects is highly relevant, because it will dictate whether this disease should be managed through immunosuppression or directed antiviral drugs."

COVID-19 should also not be ruled out, Tacke added. "Researchers should investigate the possibility that SARS-CoV-2 proteins act as 'superantigens,' triggering a powerful immune response to [adenovirus type 41] or AAV2 in a host whose immune system has been sensitized."

For their study, the researchers tested plasma, whole blood, nasal swab, and stool samples from 16 pediatric patients with cases of severe unexplained hepatitis detected in six states – Alabama, California, Florida, Illinois, North Carolina, and South Dakota -- from Oct. 1, 2021, to May 22, 2022.

They used viral polymerase chain reaction (PCR) testing, along with various metagenomic sequencing and molecular-testing methods, and compared them with a control group of 113 pediatric patients, with about half from California and Georgia to be geographically similar. All told these included 42 patients (37%) without hepatitis, 30 patients (26.5%) with acute hepatitis of defined etiology, 23 patients (21%) with acute gastroenteritis, and 18 blood donors (16%).

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