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May 5, 2022 11:11 AM EDT

Since last autumn, doctors at the Children’s Hospital of Alabama have been wrestling with a mystery. From October 2021 through February of this year, nine children—the youngest 20 months old and the oldest 5 years and 9 months—were rushed to the hospital with concerning symptoms, all of which turned out to be due to unexplained cases of acute hepatitis, also known as liver inflammation.

As the U.S. Centers for Disease Control and Prevention (CDC) recently reported, all of the patients tested negative for the hepatitis A, B, and C viruses, and also tested negative for COVID-19. They did test positive for adenovirus, a common family of at least 50 different viruses—including the common cold—that typically cause respiratory symptoms, but can also cause intestinal problems. Seven of the nine pediatric patients were suffering from vomiting or diarrhea before admission, and five of the nine tested positive for adenovirus 41—one of the strains known to affect the gut. None of the children were immunocompromised, none suffered from any other known illnesses, and all came from different parts of the state, ruling out the idea of a local infection of some kind.

In three cases, the hepatitis grew so severe that the children suffered from liver failure. Two children required liver transplants. Since then, all nine children have recovered or are recovering, but the cause of their illness remains unknown.

Alabama is not alone. In April 2022, the World Health Organization (WHO) reported that at least 169 similarly mysterious cases of hepatitis have turned up in nine countries in Europe as well as in Israel, among children ages one month to 16 years. So far, globally, one death has been reported and 17 children have required liver transplants. At least 74 of the children have tested positive for adenovirus, and 18 were diagnosed with type 41.

Read More: COVID-19 Risks for Kids Under 5 Right Now: What Parents Should Know

Cases of pediatric hepatitis have been linked to adenovirus 41 in children in the past, the WHO says, but only in those who were immunocompromised, which was not the case with any of the children in the global sample group. After the WHO issued its report in late April, Wisconsin, North Carolina, and Illinois also reported a collective nine additional cases, with one death in Wisconsin and one liver transplant in Illinois. These cases were also not mentioned in the recent CDC report.

(Update: At a May 6 press conference, the CDC provided new nationwide totals. So far, adenovirus-linked hepatitis has been seen in 109 children in 24 states and Puerto Rico. There have been five deaths; 14% of the cases required liver transplants; 90% required hospitalization.)

What is causing the outbreak?

Researchers say that active infection with COVID-19 is an unlikely link but needs further investigation. Of the 169 children assessed by the WHO as of April 21, only 20 tested positive for SARS-CoV-2—and 19 of those also had an adenovirus. “And we can rule out any type of relation to the [COVID-19] vaccine,” says Dr. Markus Buchfellner, a pediatric infectious-disease physician at the University of Alabama at Birmingham and a co-author of the CDC report. Of the nine Alabama patients, seven were ineligible for the shots and the two who were eligible had not received any doses yet.

Six of the Alabama patients did turn up positive for Epstein-Barr virus (EBV) by PCR testing, but they were negative for antibodies to the virus, suggesting that the infections were not acute, but rather what the CDC report called “low-level reactivation of previous infection.” EBV can be associated with hepatitis A, but that is not the type of hepatitis the Alabama patients had. “These children did not have EBV-related hepatitis,” Buchfellner says. The Alabama doctors also ruled out autoimmune disease.

One possible reason for these liver-inflammation cases currently under investigation is that lower circulating levels of adenovirus during pandemic lockdowns may have left children’s immune systems unprimed for how to react to the common virus. That, in turn, may be enabling adenovirus infections to overrun children’s immune systems—though exactly why that would result in liver disease remains unknown. The fact that adenovirus was found in the blood of all nine Alabama children is a powerful piece of evidence, Buchfellner says, since unless there has been a very recent infection, the bloodstream usually clears itself of the virus relatively rapidly. “In a healthy child, we would not expect to see the virus in the blood,” he says.

One problem with the adenovirus theory is that liver biopsies were conducted on all of the Alabama children, and the virus was not found in any of their liver tissue. That doesn’t mean it was never there; it’s possible for the liver to clear itself of the virus after hepatitis takes hold. Still, its absence in all of the biopsies clouds the issue. “That is the missing piece, in my opinion,” says Buchfellner. “That keeps us from saying for certain that it’s the adenovirus that caused the disease.”

It also still can’t be said with certainty that SARS-CoV-2 played no role in the disease. Acute infection was missing in the Alabama sample group and in most of the global patients, but that doesn’t rule out the possibility that a past infection might play a role. The United Kingdom Health Security Agency is looking into the possibility that affected children might have had COVID-19 in the past and that that affected their immune system in some way, making them more susceptible to hepatitis. But the research is preliminary. “My opinion is that there is not enough to know one way or the other,” says Buchfellner.

The WHO and CDC have also not ruled out the emergence of a new, yet unidentified virus that could be causing the outbreak. “Across the world, everyone is working on their sequencing of adenoviruses,” Buchfellner says. “Over the next few weeks to months, we will learn a lot more about that.”

In the meantime, parents should be alert to symptoms of hepatitis, including nausea, vomiting, stomach pain, dark urine, yellowing of the skin or eyes, fever, and fatigue. The cause of the new clusters may not yet be known, but the course of action—seeking immediate medical attention if signs of the disease appear—is clear.

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Write to Jeffrey Kluger at jeffrey.kluger@time.com.

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