Medical research: Unexplained childhood hepatitis and adeno-associated virus 2 (AAV2)

The rise in unexplained hepatitis cases among children since 2022 is linked to a common childhood virus known as adeno-associated virus 2 (AAV2), according to three studies published in Nature this week. It remains unclear whether AAV2 is the cause of the hepatitis or merely an indicator of infection by another virus.

Since 2022, more than 1,000 cases of paediatric hepatitis (inflammation of the liver) with no known cause have been reported in 35 countries, including the UK and USA. In some cases, the hepatitis was so severe that a liver transplant was needed; a smaller subset of cases were fatal. Previous analyses have found an association with human adenoviruses (common pathogens that affect humans, causing illnesses such as respiratory infections or gastroenteritis), although it has been unclear whether this link is causative.

Three independent research papers published in Nature provide evidence that infection by AAV2 is linked to the increase in unexplained childhood hepatitis. This virus is known to replicate in the liver, but not known to cause hepatitis and cannot replicate without a ‘helper’ virus.

Charles Chiu and colleagues analysed samples from 16 children with acute severe hepatitis of unknown origin from the USA and compared them with 113 control individuals. In blood from 14 patients, AAV2 was detected in 13 cases (93%), compared to 4 (3.5%) of the controls. All 14 of these patients also tested positive for human adenoviruses. In the 13 children infected with AAV2, coinfections with helper viruses (such as Epstein-Barr virus or one of the human herpesviruses in the HHV-6 group) that might promote AAV2 replication were detected. The authors suggest that the severity of the disease might be related to coinfections involving AAV2 and helper viruses.

In two separate studies, Emma Thomson and colleagues and Judith Breuer and colleagues report similar findings from the UK. The first team detected AAV2 in 26 out of 32 (81%) cases of hepatitis, versus in 5 out of 74 (7%) control individuals; the second team detected AAV2 in 27 out of 28 (96.4%) cases of hepatitis, and low rates in control individuals. Thomson and colleagues found an association between host genetics and cases of hepatitis: approximately 93% of the affected children carried a particular gene for human leukocyte antigen (a molecule that helps the immune system to recognize infected cells), compared with around 16% of the control group — a finding that suggests some children may be genetically more susceptible to some forms of hepatitis. Breuer and colleagues also detected low levels of human adenovirus and human betaherpesvirus 6B (HHV-6B), and suggest that these viruses might enable AAV2 replication, and potentially triggered immune-mediated liver damage.

Although the three papers link AAV2 infection to the recent surge in unexplained childhood hepatitis, it remains unclear what the role of this virus is in the development of liver disease. Questions remain regarding the factors that underlie the rise in hepatitis with no known origin. In an accompanying News & Views, Frank Tacke considers the part played by COVID-19 lockdowns. “The wave of hepatitis in spring 2022 coincided with the relaxation of COVID-19 measures around the globe, and cases rapidly tailed off”, he notes. “As such, the timing of the outbreak might be explained by the fact that children were suddenly exposed to a barrage of viruses after lockdowns, or had poorly trained immune systems that led to an increased susceptibility to otherwise harmless viruses,” Tacke adds.