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The CDC issued a nationwide alert over the unexplained cases of acute hepatitis in children, recommending that physicians consider in cases with an unknown etiology and report such cases to the agency and state public health authorities.

In a Health Alert Network advisory on Thursday, the agency detailed nine cases of significant liver injury seen at a large Alabama Children's hospital. Five cases involving previously healthy children initially presented in November 2021 -- three had acute liver failure and two ultimately required a transplant, but none of the children died. COVID-19 was ruled out in all of the patients and all tested positive for an adenovirus infection.

"A possible association between pediatric hepatitis and adenovirus infection is currently under investigation," the CDC said.

The Alabama hospital further identified four more pediatric patients with both hepatitis and adenovirus infection from October 2021 to February 2022 after case-finding efforts. Cases that underwent sequencing all had adenovirus type 41, which typically causes acute gastroenteritis, often accompanied by respiratory symptoms.

"While there have been case reports of hepatitis in immunocompromised children with adenovirus type 41 infection, adenovirus type 41 is not known to be a cause of hepatitis in otherwise healthy children," said CDC.

In two of the patients, results of quantitative PCR testing of plasma samples were negative, but whole blood sample testing turned up evidence of the infection.

The alert follows and other European countries of very young children with acute hepatitis who tested negative for established hepatitis viruses; some of them also had adenovirus infection.

CDC noted that over 50 types of adenoviruses can cause infections in humans. These viruses "most commonly cause respiratory illness but depending on the adenovirus type they can cause other illnesses such as gastroenteritis, conjunctivitis, cystitis, and, less commonly, neurological disease," the agency noted.

The agency is recommending nucleic acid amplification testing (PCR, for example) for adenovirus using either blood, respiratory, stool, or rectal samples. Whole blood testing should also be considered for patients who test negative on PCR on plasma samples, but present with an unknown etiology.

CDC is also requesting that past cases be reported to the agency and to state public health authorities, regardless of whether adenovirus testing was conducted -- specifically, any case since October 1, 2021 involving children under 10 who presented with elevated levels of alanine aminotransferase or aspartate aminotransferase (>500 U/L) with an unknown hepatitis etiology should be reported.

For patients who remain under medical care, any available residual specimens should be saved and frozen to allow for any additional testing.

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