San Francisco—Researchers are beginning to understand why acute, severe hepatitis that began appearing in otherwise healthy children after COVID-19 lockdowns eased in the United States and 34 other countries a year ago.

The University of California San Francisco (UCSF)–led study noted that pediatric hepatitis is rare, and it was alarming when about 1,000 cases of severe, unexplained hepatitis occurred. With approximately 1,000 cases to date, 50 of the children required liver transplants and at least 22 have died. UCSF worked with the CDC on the research.

In a report published in Nature, researchers described how they linked the outbreak to coinfections from multiple common viruses, especially a strain of adeno-associated virus type 2 (AAV2). Interestingly, they pointed out that AAVs are not known to cause hepatitis on their own but need other “helper” viruses, such as adenoviruses that cause colds and flus, to replicate in the liver.

The authors explained that once children returned to school after pandemic shutdowns, they were more susceptible to infections with those common pathogens. For a small subset, getting more than one infection at the same time might have made them more vulnerable to severe hepatitis.

“We were surprised by the fact that the infections we detected in these children were caused not by an unusual, emerging virus, but by common childhood viral pathogens,” stated senior author Charles Chiu, MD, PhD, professor of laboratory medicine and medicine at UCSF. “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,” Dr. Chiu said. “It may have been an unintended consequence of what we have experienced during the last two-to-three years of the pandemic.”

The study team used polymerase chain reaction testing, viral enrichment–based sequencing, and agnostic metagenomic sequencing to analyze samples from 16 human adenoviruses (HAdVs)–positive cases from October 1, 2021, to May 22, 2022, comparing them with 113 controls.

“In blood from 14 cases, adeno-associated virus 2 (AAV2) sequences were detected in 93% (13 of 14), compared to four (3.5%) of 113 controls (P <.001) and to 0 of 30 patients with hepatitis of defined etiology (P <.001),” the researchers explained. “In controls, HAdV-41 was detected in blood from nine (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including eight of nine patients with positive stool HAdV testing, but coinfection with AAV2 was observed in only three (13.0%) of these 23 patients versus 93% of cases (P <.001).”

The study also detected coinfections by Epstein-Barr virus, human herpes virus 6, and/or enterovirus A71 (EV-A71) in 12 (85.7%) of 14 cases, with higher herpes virus detection in cases versus controls (P <.001). “Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses,” the authors concluded.

The pediatric cases came from six states—Alabama, California, Florida, Illinois, North Carolina, and South Dakota—from October 1, 2021, to May 22, 2022.

Dr. Chiu noted that the results were similar from other studies in the United Kingdom, adding that all three studies identified coinfections from multiple viruses, and 75% of the children in the U.S. study had three or four viral infections.

While the clusters of acute severe hepatitis in children have recently waned, Dr. Chiu urged that children wash their hands frequently and stay home when sick to avoid viral outbreaks.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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