Scientists May Have Found the Culprit Behind Mysterious Hepatitis Outbreaks in Kids

Several teams of scientists believe they have uncovered the likely cause of a mysterious surge of severe hepatitis last year that hospitalized and killed children around the world. In three studies published this week, the groups detail evidence that a common but usually not pathogenic virus was strongly associated with the cases, likely aided by co-infection with other common viruses. The affected children might have been genetically unlucky as well.

Early last year, health officials from the UK first reported on a cluster of severe hepatitis, with cases dating to fall 2021. Hepatitis is a catch-all term for liver inflammation, often accompanied by symptoms like fever, fatigue, and jaundice (yellowed skin and eyes); in severe cases, it can lead to outright liver failure or death. These children hadn’t tested positive for any known causes of hepatitis, including the group of unrelated viruses named after the condition.

Before long, other places would report similar clusters. By July 2022, according to the World Health Organization, over 1,000 cases of this severe, unexplained childhood hepatitis were documented across 35 countries. Most children were hospitalized; about 5% became so sick that they needed a liver transplant; and 2% ultimately died as a result.

There have been various theories as to the origin of these clusters. Many but not all children tested positive for adenoviruses, commonly encountered microbes that can cause illness; some also recently had SARS-CoV-2, the cause of covid-19. But the harm caused by these viruses usually doesn’t involve the kind of severe liver damage seen in these children, indicating that some other catalyst was in play here. One debunked theory blamed the covid-19 vaccines, but many of the affected children were too young to have received the shots.

In three papers published this week in Nature, independent teams of scientists describe evidence pointing to a common suspect, albeit one that didn’t work alone: adeno-associated virus type 2 (AAV-2). Each group found that the vast majority of cases they studied had recently been infected by AAV-2, and at much higher rates than similarly matched control patients or patients who developed hepatitis from known causes. Some of the teams also found signs of AAV-2 infecting the children’s livers and indirect evidence that the organ was harmed as a result.

AAV-2 is strange, even among microbes. It’s a satellite virus, meaning that it can only make more of itself inside a cell when another “helper” virus is infecting that same cell. As the name implies, adenoviruses are a common helper virus for AAV-2, but herpesviruses can be its partner as well. In many of these children, the scientists found these helper viruses too, and sometimes even more than one.

The AAV-2 isolated from the affected children doesn’t appear to be genetically different in any important way from other known strains, but one study from UK researchers suggests another key factor behind the clusters: most of their cases carried the same variant of a gene that’s known to influence our immune response, and at a higher rate than the general population. It’s possible that carrying this variant made the children more vulnerable to the unlikely scenario that led to their hepatitis, the authors say.

“It may turn out that in rare cases, you have kind of a perfect storm of events, where there’s a subset of children who were uniquely susceptible,” Charles Chiu, an infectious disease specialist at the University of California, San Francisco and one of the authors behind the study looking at U.S. children, told the New York Times.

These studies alone aren’t proof that AAV-2 is to blame for the clusters. For one, they’re all based on a small sample of patients, and only from two of the many countries where cases were reported (the U.S. and UK). There are still unanswered questions about how exactly AAV-2 can do this to children, and we also don’t know why these clusters emerged when they did.

It’s possible that the relative lack of other common infections during the first years of the pandemic led to an immunological gap, such that outbreaks of these diseases (and their rare complications) were temporarily larger than usual once people started regularly socializing again. Yet data from the U.S. has indicated that the documented rate of unexplained hepatitis cases in children didn’t increase last year from its pre-pandemic baseline. In other words, AAV-2 may have always been a rare but consistent cause of hepatitis, but we only now noticed it because we were finally looking for it. It’s also possible that some countries did experience a genuine surge last year, while others didn’t.

Thankfully, the reported incidence of these unexplained hepatitis cases has dropped substantially since the peak last summer, so the immediate crisis seems to be over. But more research will have to be done to confirm what these scientists have found, as well as to better understand exactly what happened to these children and whether we can do something to prevent or reduce the risk of similar cases in the future.