At least one child has died of unexplained liver inflammation in a growing international outbreak of puzzling hepatitis cases in children, according to the World Health Organization.

The outbreak tally has reached more than 170 cases in 12 countries and is expected to continue growing. At least 17 children—10 percent of the cases—have required liver transplants. The ages of the affected children range from one month to 16 years, though the majority are children younger than 10 and many younger than 5.

Over the weekend, the WHO reported 114 cases in the United Kingdom, 13 in Spain, 12 in Israel, six in Denmark, fewer than five in Ireland, four in the Netherlands, four in Italy, two in Norway, two in France, one in Romania, and one in Belgium. The WHO also noted nine cases in the US, all in Alabama. But two additional cases were reported in North Carolina last week, bringing the US total to at least 11. Two of the US cases resulted in transplants.

WHO did not report the age or nationality of the child who died, but no deaths have been reported in the US.

Medical mystery

Although the global case count may seem low, severe liver inflammation (aka hepatitis) is uncommon in young children. Health officials in Scotland—who first sounded the alarm over the unexplained cases—realized something was amiss when they saw 13 cases of severe hepatitis in children just in March and April. Usually, Scotland records fewer than four such cases over an entire year.

Health experts around the world are working to understand what’s causing the severe liver injuries. Affected children have consistently tested negative for viruses that attack the liver, namely hepatitis viruses A, B, C, D, and E. So far, there’s no clear link between the cases, nor an association with travel, or a clear connection to an environmental, drug, or food exposure. The vast majority of the cases had not received COVID-19 vaccines, ruling out that possibility.

The primary suspect continues to be an adenovirus, though the common family of viruses are not known to cause hepatitis in healthy children. Of the roughly 170 cases reported, at least 74 have tested positive for an adenovirus, with 18 specifically testing positive for adenovirus type 41.

More than 50 distinct adenoviruses are known to infect humans, but they’re typically associated with respiratory, eye, and sometimes gastrointestinal and disseminated infections. Some adenoviruses have, on occasion, been linked to hepatitis, but generally only in immunocompromised children.

Adenovirus type 41, which has not been linked to hepatitis, typically causes diarrhea, vomiting, fever, and respiratory symptoms, the WHO notes. Based on data from cases in the UK, the most common symptoms of the kids affected by the outbreak include jaundice, vomiting, and abdominal pain, and most cases did not have a fever.

Working hypotheses

The international outbreak comes as the UK and the Netherlands have documented rises in adenovirus infections in the general community, driven by people resuming normal activities that were restricted during the pandemic. As such, some experts have hypothesized that the hepatitis cases could merely be a rare outcome that has always been possible from a common adenovirus—but the rare outcome appears more common now because many immunologically naïve children are getting adenoviruses at the same time following the pandemic. Still, there’s also the possibility that a novel type of adenovirus has emerged and explains the hepatitis cases.

It’s also possible it’s not due to an adenovirus at all. Some data suggests that many children who have tested positive for an adenovirus have only low levels of the virus present in their bodies. This data raised the possibility that the presence of adenoviruses is simply incidental—reflecting high transmission in the community, not the cause of hepatitis.

Further, it’s also possible that an adenovirus is just part of the story, and a co-infection may explain the unusual cases. One possibility is that a co-infection of SARS-CoV-2 and an adenovirus is behind the cases. The WHO noted that 20 children tested positive for SARS-CoV-2 and found another 19 to have a co-infection of SARS-CoV-2 and adenovirus. But researchers are also not ruling out the possibility that the liver injuries are a rare outcome from an omicron infection alone or an infection with a yet unidentified SARS-CoV-2 variant.

The WHO and other experts call for more awareness, testing, and data sharing worldwide to unravel the mystery.