Public health officials in the United States are investigating liver inflammation cases in at least 109 children as part of a mysterious hepatitis outbreak with an unknown cause. Most of the cases have led to hospitalizations and five kids have died.

American and European public health experts are among those trying to figure out what role, if any, adenovirus might play in causing the illness.

In their latest media briefing, officials from the Centers for Disease Control and Prevention said 90% of the affected children — average age 2 — required hospitalization. And 14% of them need a liver transplant.

Hepatitis literally means liver inflammation, and five types of viral hepatitis have been identified, along with the viruses that cause them. Yet none of the children tested positive for those, designated hepatitis A, B, C, D or E. Now experts are exploring whether an adenovirus — typically responsible for cold symptoms or gastric distress but not usually expected to cause hepatitis in children who are not immune-compromised — led to the inflammation and liver injury. All the children were healthy prior to having hepatitis, but many of them tested positive for adenovirus.

One strain of adenovirus, designated adenovirus 41, is of particularly high interest, but officials are quick to point out they haven’t proven adenovirus caused the recent hepatitis cases. And if it did, they are not sure how.

Dr. Jay Butler, CDC deputy director for infectious diseases, listed 25 states with cases under investigation as part of the clusters concerning health officials: Alabama, Arizona, California, Colorado, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Michigan, Minnesota, Missouri, North Carolina, North Dakota, Nebraska, New York, Ohio, Pennsylvania, Texas, Washington, Wisconsin and Puerto Rico. Over the weekend, Maryland and Hawaii also reported cases. Cases have also been identified in multiple other countries, dating back to October 2021.

“We don’t yet know their cause, but here and across the globe there are a variety of hypotheses,” said Butler, who noted that because of the link to adenovirus, that tops the “list of viruses of interest.”

He said experts have not determined if adenovirus is directly responsible or if the hepatitis was caused by an immune response to it — or if it plays some other role. Experts are investigating other infectious or environmental factors, too.

They are also “seriously considering” whether or not similar cases may have occurred at a low level for a number of years but is now more recognizable this year because efforts to contain the COVID-19 pandemic reduced the number of infections, making these clusters more noticeable, Butler said.

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Dr. Umesh Parashar, chief of the CDC’s viral gastroenteritis branch, said the situation keeps changing, but in the United Kingdom alone, more than 160 cases are being validated. Globally, there are “clearly” over 200 cases outside the United States, he said, and experts are looking at drugs, toxins, environmental exposures and other pathogens as possible causes.

They’re interested in hepatitis cases in children under 10 who test negative for the known viruses that cause hepatitis as potentially belonging in their investigation

The hepatitis cases are not linked to vaccination against COVID-19. Not one of the children was vaccinated — and the vast majority were too young to be eligible for vaccination at the time of their illness.

Butler said it may take public health experts time to assess the cases and learn more, but parents and clinicians are being asked to help.

Parents should watch for signs of liver distress, including nausea, vomiting, yellow skin and eyes, dark urine and light stool.

Utah state epidemiologist Dr. Leisha Nolen, who is both a physician and a Ph.D., recently told the Deseret News that most children who require medical care have severe vomiting and diarrhea. “But I think most parents know vomiting and diarrhea are very common in little kids. Most of the time, that’s nothing and I don’t think parents need to be concerned,” she said. But if it persists or is severe, medical attention is needed.

Butler said parents should make sure their kids are current on vaccinations. Parents and children should also take precautions normally cited to stop the spread of infection, like washing hands, avoiding people who are sick and not touching eyes, nose or mouth.

Clinicians treating children with suspected hepatitis who test negative for the common viral strains should consider testing them for adenovirus, Butler said.