Twenty-four U.S. states and Puerto Rico have reported cases of children’s hepatitis with no known cause, bumping the total number under investigation to 109, health officials announced today.

There have been five reported deaths among the cases and 14% of the patients needed liver transplants, the Centers for Disease Control and Prevention said today. About half of the suspected cases were linked to adenovirus, which the agency said is at the “top of the list” of viruses of interest.

“What makes this unusual is not the number of cases, but the possible association with adenovirus,” Jay Butler, CDC deputy director for infectious diseases said in a call with reporters.

(Hawaii was not among the 24 states with reported cases.)

CDC’s disease-trackers still don’t know whether it’s the virus itself, an immune reaction to the strain of adenovirus, or if there’s an infectious or environmental factor that may be contributing to the cases, Butler said.

Concern about the mysterious cases of pediatric hepatitis has been growing since the CDC issued an alert in April regarding a cluster of nine cases in Alabama. Additional information released last week showed none of the kids had COVID-19, but officials said today that antibody testing was not performed to look for evidence of a prior infection.

In their description of the Alabama cluster, health officials noted that several children had tested positive for adenovirus type 41, a pathogen that usually causes acute gastroenteritis — sometimes called stomach flu — leading to nausea, vomiting, diarrhea and sometimes more severe symptoms. Last week, health officials confirmed that all five patients whose samples were sequenced showed signs of the same virus type, raising the possibility of a causal link.

A group of five viruses – known as hepatitis A, B, C, D and E – are well known to cause liver disease, but others can damage the organ. Adenovirus was previously only thought to cause hepatitis in children with underlying health issues, but last week’s CDC report noted that it “might be an underrecognized contributor to liver injury among healthy children.”

“One of the things that does seem to be unusual in this instance is that many of the children who are affected, all of them among the nine in Alabama, did not have immunocompromising conditions,” Butler said.

More than 200 cases of unexplained hepatitis in kids have been identified all over the world; the U.K. alone has confirmed more than 160. Experts there are currently conducting a formal epidemiological study to determine whether adenovirus is causing the liver ailments, but are still considering other hypotheses, as well. The U.K. Health Security Agency says it is also investigating whether SARS-CoV-2 could be linked to the cases and looking at kids’ immune systems.

COVID IN PLAY

Experts have said it’s too soon to rule out the coronavirus as a cause of the cases, despite the CDC reporting none of those in Alabama were linked to the virus. COVID has been shown to damage a variety of organs, including the liver, and long COVID, especially in kids, is still poorly understood. Half a million kids are estimated to be suffering from long COVID, with varying degrees of severity and symptoms.

Zachary Rubin, a pediatric immunologist at Central DuPage Hospital in Illinois, said data released by the CDC doesn’t fully rule out a role for COVID-19 because the kids weren’t tested for antibodies that would indicate an earlier infection. Also, there were no signs of the adenovirus in the children’s livers.

The agency has also ruled out the COVID-19 vaccine as a potential cause because none of the kids were found to have been immunized, in most cases because they were too young to be eligible.

“The COVID vaccine is not the cause of these illnesses,” Butler said. “We hope this helps clarify some of the misinformation circulating online.”

SPOTTY SURVEILLANCE

So far, overall numbers of U.S. pediatric hepatitis cases haven’t increased, health officials said. However, before these cases started cropping up, the CDC only tracked pediatric hepatitis linked to known liver viruses.

Hepatitis doesn’t occur frequently in kids, but is not necessarily rare, said Saul Karpen, a pediatric liver expert at Children’s Healthcare of Atlanta and board member of the American Association for the Study of Liver Diseases. Karpen said that about 10% of his pediatric patients with liver transplants have disease that wasn’t caused by one of the recognized liver viruses.

Adenovirus is also quite common, especially in kids, who usually catch several viruses every year. It normally causes cold and flu-like symptoms. Neither adenovirus nor adenovirus type 41 are routinely tracked in the U.S., officials said today.

“We know this update may be of concern, especially to parents and guardians of young children,” Butler said. “It’s important to remember that severe hepatitis in children is rare, even with the potential increase in cases that we’re reporting today.”

The agency is urging clinicians to continue performing standard diagnostic procedures for children with acute hepatitis and recommending that clinicians evaluate these patients and consider testing for adenovirus.