Coinfection with two common viruses, adenovirus and adeno-associated virus 2 (AAV2), may be behind the hepatitis cases that began appearing in children worldwide in April, according to two studies posted on medRxiv, a preprint server. (The research has not yet been published in a peer-reviewed journal.) These viruses usually cause only mild illness, but it is thought that coinfection along with certain genetic factors may have triggered an acute liver inflammation. The outbreak has led to more than 1,000 cases worldwide, with 46 children needing liver transplants and at least 22 deaths.

The two studies—one from researchers at University College London's Great Ormond Street Institute of Child Health and the other from scientists at the University of Glasgow Centre for Virus Research—sequenced samples from children with acute hepatitis and from matched controls. In both studies, AAV2 was detected in cases that required transplants as well as in most hospitalized cases, but in very few of the matched healthy controls or hepatitis cases with known causes.

AAV2 needs a “helper” virus to replicate, and the researchers found helper viruses such as adenovirus and human herpesvirus 6B in almost all the children with unexplained hepatitis. In addition to the presence of these viruses, the researchers discovered the presence of the human leukocyte antigen gene, which may contribute to the development of severe illness.

The role of adenovirus in this outbreak has been a key focus of epidemiological investigations. While this common virus usually causes only benign infections, young children have missed exposures to viruses from other children due to schools being closed during the COVID-19 pandemic and other isolating restrictions. This might have led to an atypical immune response from postpandemic exposure. Notably, since November 2021 there has been a fourfold increase in adenovirus infections compared with infection rates before and during the pandemic.

According to the World Health Organization, 76% of the children who developed hepatitis are under six years of age. The most common initial symptoms have been nausea and vomiting, jaundice, and abdominal pain. Because the outbreak has affected only a small number of children worldwide, clinicians and researchers stress that global coordination among investigators will be necessary to further understand and confirm the origins of the disease.—Betsy Todd, MPH, RN