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Over 100 cases of pediatric hepatitis of unknown cause are under investigation in 25 states, and five children in the U.S. have died in the past seven months from the condition, CDC researchers said on Friday.

The agency is retrospectively reviewing 109 cases of this unusual hepatitis in children, dating back to October 2021 when the first cases were reported in Alabama, said Jay Butler, MD, CDC's Deputy Director for Infectious Diseases, at a press briefing.

The definition of cases under investigation includes all children younger than 10 with hepatic transaminase levels above 500.

Cases were severe, with over 90% of children hospitalized and 14% requiring liver transplants, he added. Children were young, with a median age of 2. Butler noted that there has not been a significant increase in liver transplants in the U.S., nor has CDC's sentinel surveillance detected an increase in the number of emergency department visits made for pediatric hepatitis.

Adenovirus was detected in "more than half" of the U.S. cases, said Butler, and remains a suspect. Adenovirus 41 is one of the only strains of the virus that affects the gastrointestinal tract.

"Adenovirus was detected in some children, but we don't know if it was the actual cause of this illness," Butler said.

He reiterated that what remains unusual about these cases is not that they are pediatric hepatitis, but that they are pediatric hepatitis associated with adenovirus. While this condition occurs in immunocompromised children, "many" children who were affected, including the initial nine in Alabama, did not have immunocompromising conditions, Butler noted.

CDC is investigating several possibilities, he said, including an "immune reaction to a strain of adenovirus" and "infectious/environmental co-factors," such as animal exposure.

Of course, there is another virus that has been on the minds of the public for the last 3 years, which multiple children have been exposed to, but Butler seemed to downplay COVID infection as a cause, since none of the children tested had active COVID infection.

He did not rule it out as a confounding factor, however, calling it "a hypothesis we continue to pursue."

There may be "serologic evidence of past infection that may not have been clinically apparent," Butler said. "The question is still unanswered."

Another hypothesis could be that this potential adenovirus-related hepatitis occurs "at a low level" in regular years but is more recognizable this year.

"Because of the decrease in the number of infections over the past 3 years due to [COVID] mitigation efforts," we may be seeing "some catch-up infections as community mitigation efforts are being lessened," Butler noted.

Butler urged clinicians to follow updated CDC guidance when investigating potential cases of hepatitis in children, which includes performing a regular diagnostic workup, but also to consider testing for adenovirus. As always, all cases should be reported to the state health department.

CDC is examining not only pediatric hepatitis trends, but trends in adenovirus over the past several years as it continues to investigate this issue, Butler said.

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