In recent months there have been dozens of reported cases of severe hepatitis in young children in which the cause is of unknown origin.

In an outbreak report on 23 April, the World Health Organization stated that 12 countries have reported at least 169 cases of hepatitis of unknown origin in children. The age range of cases is 1 month to 16 years old. Seventeen of the children have undergone liver transplants and at least one has died. None of the viruses that cause acute viral hepatitis (hepatitis viruses A, B, C, D and E) have been detected in any of the 169 cases.

The United Kingdom has had the greatest number of reported cases so far, with 108 cases as of 21 April according to the UK Health Security Agency. 77% of cases have tested positive for adenovirus. None of the confirmed cases is known to have received a COVID vaccine.

In the United States, the state of Alabama was the first to report cases. All nine of the reported cases have tested positive for adenovirus according to the U.S. CDC. Five of these were sequenced, and adenovirus type 41 infection was identified in all five. Adenovirus type 41 is known to commonly cause pediatric acute gastroenteritis, but is not known to be a cause of hepatitis in otherwise healthy children.

Currently the leading hypothesis for the causative agent involves adenovirus, with either an already-circulating variant severely impacting immunologically naive young children or there being a new variant with a more severe clinical profile. The former may be the result of less social mixing during the COVID pandemic. However, public health officials have emphasized that other hypotheses have not been ruled out. Other hypotheses include COVID infection or an unidentified toxin. Some have suggested COVID vaccination may be a cause and a recent paper has found that mRNA vaccine can enter a human liver cell line in vitro: "Our results indicate a fast up-take of BNT162b2 into human liver cell line Huh7, leading to changes in LINE-1 expression and distribution."