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Severe acute hepatitis in children: uncertainty persists over causes and novelty

Keith Alcorn
24 May 2022

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, 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 (ECDC) 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.”

In the United Kingdom, 197 cases had been identified in children under 16 by 16 May. Of these, 170 have been tested for adenoviruses and 68% tested positive. Genotyping of the adenovirus has been carried out in 35 cases and 77% show the 41F variant. SARS-CoV-2 has been detected in 25 cases.

ECDC reports that 125 cases had been reported by 19 May in the European Union and EEA area (excluding the UK). The largest numbers of cases have been reported in Italy (35) and Spain (26).

Outside of the EU/EEA and the United Kingdom, at least 313 cases of acute hepatitis of unknown origin among children have been reported by 16 countries by 19 May.

Of these, 180 had been reported in the United States by 18 May. The US Centers for Disease Control and Prevention (CDC) investigation found cases going back to October 2021. Six deaths and 15 liver transplants have occurred in children with acute hepatitis in the United States. The US CDC says that adenovirus has been detected in approximately half of cases.