Severe acute hepatitis of unknown cause in children: an update

The possible causes of cases of severe acute hepatitis in children continue to puzzle scientists and further work is needed to establish whether all countries are seeing unusual levels of severe liver disease in children, a webinar organised by the European Association for the Study of the Liver (EASL) heard this week.

An unusual level of cases of severe acute hepatitis in children began to be reported in the United Kingdom in late March. Since then, surveillance in Europe and North America has identified further cases in over 30 countries.

It is unclear if the cases have a single cause. Interest focuses on adenovirus infection, especially variant 41, which causes gastrointestinal illness. Another hypothesis is that prior infection with SARS-CoV-2 – or incomplete elimination of SARS-CoV-2 infection – leads to a heightened risk of severe immune reaction to adenovirus infection. Research is also ongoing into potential environmental, drug or toxin exposures.

Several proposed causes have been dismissed:

  • Viral hepatitis: all children have tested negative for viral hepatitis.
  • Current SARS-CoV-2 infection: investigations in Britain and Europe have failed to detect the virus in most children affected.
  • SARS-CoV-2 vaccination adverse reaction: the vast majority of children had not been vaccinated. A large proportion of cases has occurred in children under the age of 5, who are not eligible for vaccination.
  • Exposure to dogs: the UK Health Security Agency has ruled out exposure to pet dogs after an early suggestion that children with acute hepatitis were much more likely to have contact with dogs.
  • Paracetamol: known to cause acute hepatitis, paracetamol has been detected in some cases at therapeutic doses but there is no evidence of toxicity.

Further careful investigation is needed to test various hypotheses about causes. It is also important to bear in mind that the rise in cases may simply be a consequence of greater vigilance and prompt reporting of cases. A survey of 34 paediatric liver clinics in 22 European countries and Israel, carried out in April, found no increase in the rate of acute liver failure cases in children in the first four months of 2022 compared to the same period in 2019-2021. The European Reference Network on Hepatological Diseases (ERN RARE-LIVER), which links researchers on rare liver conditions, says that the findings of the survey “do not confirm the alarming observations from the UK.”

Erika Dufell of the European Centre for Disease Prevention and Control told an EASL webinar that there was considerable variation between European countries and that four out of eight European countries that have examined their data in detail say that the number of cases is above the normal rate. Philippa Easterbrook of the World Health Organization noted that the United Kingdom and the United States account for two-thirds of reported cases so far and “a few countries have reported a signal above the background rate.”

Related links

UK emergency department screening for viral hepatitis feasible and acceptable