Investigators found most cases were infected with adeno-associated virus 2 and a helper virus, though it’s unclear what role the former plays.
A new analysis of pediatric cases of hepatitis with unknown etiology shows a high number of patients are infected with adeno-associated virus 2 (AAV2) and at least one helper virus.
The report, which was published in Nature, raises questions about the role—if any—that AAV2 plays in the pathogenesis or severity of hepatitis.
Over the past 18 months, clusters of children with acute non-A-E severe hepatitis with unclear causes have been reported in 35 countries, noted corresponding author Charles Chiu, MD, PhD, of the University of California, San Francisco, and colleagues.
Human adenoviruses (HAdVs) are one potential cause of hepatitis, though Chiu and colleagues said cases are thought to be rare in children with un-compromised immune systems and no underlying comorbidities. They said HAdVs have been found in clusters of children with hepatitis in the US, Scotland, and the United Kingdom, though it is not known whether the virus was the cause of the cases. Adeno-associated viruses (AAVs) have also been identified in at least one study of children with acute severe hepatitis. However, AAVs cannot cause hepatitis on their own.
“Importantly, AAVs require a helper virus, such as a herpesvirus or adenovirus, for productive infection of liver tissue,” Chiu and colleagues wrote.
In an effort to better understand potential causes of these unknown-etiology clusters of acute severe hepatitis, the investigators conducted polymerase chain reaction (PCR) testing, viral enrichment-based sequencing, and agnostic metagenomic sequencing on samples from 16 patients with HAdV-positive hepatitis collected between October 2021 and May 2022. They performed the same tests on 113 controls.
The investigators found that AAV2 sequences in the blood of 13 of 14 blood samples (93%) from patients with hepatitis, compared to just 4 of the 113 controls (3.5%; p<0.001). Among samples from 30 cases of hepatitis with defined etiology, none were found to have AAV2.
Coinfection with HAdV-41 was also present in 93% of hepatitis cases, the authors said. Among 23 patients with acute gastroenteritis without hepatitis, 9 patients (39.1%) were found to have HAdV-41 infection, but only 3 of the 23 patients (13.0%) had co-infection with HAdV-41 and AAV2.
Coinfection with other viruses, including Epstein-Barr virus, human herpesvirus 6, and enterovirus A71 were also common among the 14 cases analyzed.
“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 acute hepatitis, although a direct causal link has yet to be confirmed,” the investigators said.
The exact role of AAV2 is not clear, the authors said, but it may be that co-infection with AAV2 causes, or is associated with, more severe disease.
“Importantly, AAV2 was only seen in 2 (16.7%) of 12 pediatric controls with HAdV-associated acute gastroenteritis in the absence of liver inflammation, suggesting that co-infection with AAV2 may predispose patients to more severe disease,” Chiu and colleagues said.
The authors said their study had a number of limitations, including incomplete availability of liver biopsies, low titers associated with detected viral antigens, and the study’s retrospective nature.
Yet, they said their results are consistent with findings from studies in the United Kingdom and Scotland.
“AAV2 infection may contribute to the pathogenesis and/or severity of the hepatitis,” they concluded, “or alternatively, may be a non-pathogenic marker of liver inflammation.”
They said further study will be needed to better understand how AAV2 is involved in these cases.
Servellita V, Gonzalez AS, Lamson DM, et al. Adeno-associated virus type 2 in US children with acute severe hepatitis [published online ahead of print, 2023 Mar 30]. Nature. 2023;10.1038/s41586-023-05949-1. doi:10.1038/s41586-023-05949-1