The CDC is investigating "hepatitis of unknown cause" in 109 children, including five deaths, agency officials said in a May 5 update.
The cases occurred in children across 25 states and territories since October.
More than 90 percent of the children were hospitalized, and 14 percent required liver transplants. They had a median age of 2. Most of the children have fully recovered. More than half had adenovirus infections, which is being examined as a potential factor in the cases, though no conclusions could be drawn about the cause.
Adenoviruses are common and usually cause a range of flu-like symptoms, including stomach and intestinal symptoms.
Officials emphasized severe hepatitis is rare in otherwise healthy children.
"It's important to remember that severe hepatitis in children is rare even with the potential increase in cases that we're reporting today," said Jay Butler, MD, the CDC's deputy director for infectious diseases.
There's no evidence that COVID-19 infection or vaccination are linked to the cases, the CDC officials said. The World Health Organization in an earlier update ruled out the COVID-19 vaccine as a potential cause in 228 probable cases of severe hepatitis in children in 20 countries, as most hadn't been vaccinated.
The CDC's Dr. Butler said it's an "evolving situation" and the agency is "casting a broad net" as it works to determine the cause.
Aside from adenovirus, the agency is also considering "environmental exposures, medications or other infections that the children might have," Dr. Butler said.
The agency first issued a nationwide health alert regarding hepatitis in children April 21, saying it was working with health officials in Alabama to investigate a cluster of nine cases, all of whom tested positive for adenovirus, that occurred in children about ages 2 to 6 in the state.