Is adenovirus responsible for the hepatitis outbreak in children?

The cause of the hepatitis outbreak in children across the United States and Europe remains a mystery, with over 100 cases of concern identified in the United States (US). Some cases have been associated with adenovirus infection, and the US Centers for Disease Control and Prevention's (CDC) current health advisory advises physicians to test all children with acute hepatitis of unknown etiology for adenovirus.

The outbreak first came to attention on April 12, 2022, when the European Centre for for Disease Prevention and Control reported 70 cases of "severe acute hepatitis" in previously healthy children under the age of 16, most between the ages of 2 to 5 years, across England and Scotland in the weeks prior. Most children presented with jaundice, though some presented with vomiting. All had significantly elevated liver transaminases (>500 U/L) and negative testing for known hepatitis viruses (hepatitis A, B, C, D, and E). Some (exact figures not provided) had positive SARS-CoV-2 tests, and some had positive adenovirus tests.

A few days later, on April 21, 2022, the US CDC issued a health advisory regarding a cluster of similar hepatitis cases at a children's hospital in Alabama: "Case-finding efforts at this hospital identified...a total of nine patients admitted from October 2021 through February 2022; all five that were sequenced had adenovirus type 41 infection identified." All of these children were previously healthy, all tested negative for hepatitis A, B, and C, and all tested negative for SARS-CoV-2 infection. That same day, the CDC issued a health alert, requesting that physicians "report any suspected cases of hepatitis of unknown origin to their local and state health departments."

A CDC Mortality and Morbidity Weekly Report (MMWR) last week reviewed the details of the 9 cases in Alabama. The children were from different areas of the state and were not otherwise connected:

Elevated transaminases were detected among all patients (alanine aminotransferase [ALT] range = 603–4,696 U/L; aspartate aminotransferase [AST] range = 447–4,000 U/L); total bilirubin ranged from normal to elevated (range = 0.23–13.5 mg/dL, elevated in eight patients). All patients received negative test results for hepatitis viruses A, B, and C, and several other causes of pediatric hepatitis and infections were ruled out including autoimmune hepatitis, Wilson disease, bacteremia, urinary tract infections, and SARS-CoV-2 infection. None of the children had documented history of previous SARS-CoV-2 infection.

Cases have now been documented in additional European countries as well as Israel. Going forward, the more data the CDC can gather, the greater its chances of solving this puzzle - and, potentially, identifying treatment and/or mitigation measures to benefit patients. Physicians in the US can help by:

1. Notifying the CDC (ncirddvdgast@cdc.gov) and/or your state health department "of children <10 years of age with elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) (>500 U/L) who have an unknown etiology for their hepatitis (with or without any adenovirus testing results, independent of the results) since October 1, 2021."
2. Testing children with hepatitis of unknown etiology for adenovirus 41: "NAAT (e.g. PCR) is preferable and may be done on respiratory specimens, stool or rectal swabs, or blood." 

If you'd like to refresh your knowledge regarding hepatitis, there's an AFP By Topic on Hepatitis (and Other Liver Diseases) that includes comprehensive overviews of diagnosis and treatment.