Surface of the AAV-2 serotype of the adeno-associated virus, with one of the five-fold axes centered. Derived from the 3-A crystal structure, 1LP3. Credit: Jazz LW
Last spring, just as the COVID-19 pandemic began to wane to an endemic level, U.S. states and other countries were hit with yet another mysterious virus. This virus, however, was killing young children rather than presenting asymptomatically as SARS-CoV-2 did.
In April 2022, the World Health Organization reported upward of 200 cases of severe acute hepatitis of unknown origin in multiple locations throughout Europe. Just days later, the U.S.-based CDC issued a similar public health advisory regarding an unusual cluster of children aged 1 to 6 diagnosed with severe hepatitis and adenovirus infection.
All of the children were previously healthy, and none had a recent SARS-CoV-2 infection. At the time, no U.S. deaths were reported, though two of the pediatric patients required a liver transplant. By time the hepatitis outbreak ended in Winter 2022, it infected about 1,000 children—22 fatally, with an additional 50 needing liver transplants.
Now, researchers at UC San Francisco have linked the outbreak not to a novel virus, but to co-infections from multiple common viruses, in particular a strain of adeno-associated virus type 2 (AAV2). AAVs are not known to cause hepatitis on their own. They need “helper” viruses, such as adenoviruses that cause colds and flus, to replicate in the liver.
“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,” said senior author Charles Chiu, MD, PhD, professor of laboratory medicine and director of the UCSF Clinical Microbiology Laboratory. “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. It may have been an unintended consequence of what we experienced during the last two to three years of the pandemic.”
For the study, published in Nature, the researchers used PCR, various metagenomic sequencing and molecular testing methods to analyze plasma, whole blood, nasal swab and stool samples from 16 pediatric cases in six states—Alabama, California, Florida, Illinois, North Carolina and South Dakota—from Oct. 1, 2021, to May 22, 2022. The specimens were compared with 113 control samples.
According to the results, human adenoviruses (HAdVs) were found in all the cases, while AAV2 was detected in 93% of the cases. Additionally, a specific type of adenovirus linked to gastroenteritis (HAdV-41) was found in 11 cases. Co-infections with Epstein-Barr, herpes and enterovirus were found in 86% of cases.
Two concurrent studies in the UK also identified the same AAV2 strain that Chiu and his team found. In fact, all three studies identified co-infections from multiple viruses, with 75% of the U.S. pediatric sample harboring three or four viral infections.
Since AAVs are not considered pathogenic on their own, the researchers could not establish a direct causal link with severe acute hepatitis. However, they caution that children may be especially vulnerable whenever they have other infections.
While infections from adeno-associated viruses can occur at any age, the peak is typically between 1 and 5 years old. The median age of the infected children in the study was 3 years old.
The clusters of acute severe hepatitis waned in early Winter 2022, and health authorities have not seen unusual or concerning numbers in 2023 thus far.