Acute pediatric hepatitis of unknown origin

Everything you need to know about the surveillance system established to monitor cases of severe acute pediatric hepatitis of unknown origin reported in France and internationally. Status updates and a summary of the cases investigated.

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Following the report shared by the United Kingdom regarding cases of severe acute hepatitis of unknown origin in young children in early April 2022, a specific reporting system for potential cases was quickly established in France to detect any similar trend within the country. Given the absence of an excess of cases identified in France and the very significant decrease in the number of cases reported by the United Kingdom since June 2022, this specific case reporting system has been suspended since October 1, 2022; however, syndromic surveillance and collaboration with pediatric hepatologists, hepatologists, and virologists are maintained to detect any unusual signals.

On April 5, 2022, the United Kingdom reported to the World Health Organization (WHO) an unusual increase in severe acute hepatitis of unknown origin among otherwise healthy children under the age of 10. These cases of hepatitis were not caused by hepatitis A, B, C, Delta, or E viruses, and the other most common causes of acute hepatitis were not identified (drug-related causes, immune dysfunction, etc.).

Upon receiving this alert, Santé publique France contacted its partners in the national public health network: the Francophone Group for Pediatric Intensive Care and Emergency Medicine, the French Society of Pediatrics, the French Society of Hepatology, and the National Reference Centers for Hepatitis B/C/Delta, Hepatitis A/E, gastroenteritis viruses, and respiratory infection viruses. A group of experts comprising pediatric hepatologists from the four pediatric liver transplant centers in France (Necker, Bicêtre, Marseille, Lyon), hepatologists, virologists, and epidemiologists was thus formed.

A reporting system for potential cases was established in France to detect any similar signals nationwide, describe, and investigate any detected cases. A case definition, guidelines for action, and status updates were developed and made available on our website throughout the investigations. Several potential cases have been reported by medical teams since the surveillance system was implemented nationwide.

Cases of acute pediatric hepatitis: Update as of October 1, 2022, in France and internationally

In France:

Ten possible cases have been reported since May 3, 2022. These involved 4 girls and 6 boys aged 2 months to 14 years who presented with acute hepatitis between January 1 and July 7, 2022. Six children had at least one positive microbiological test for adenovirus, with or without a known underlying condition or one currently under investigation; one had a SARS-CoV-2 infection; and for the other three, no cause was identified during the recommended initial evaluation. None of these children underwent a transplant, and none died. For 4 of the 10 children, additional analyses (metagenomic analyses) failed to identify another pathogen that could have caused acute hepatitis.

The majority of reports received by Santé publique France concerned children with known underlying conditions or conditions currently under investigation and therefore did not meet the case definition associated with the international alert. These findings differed from those observed in the United Kingdom, where the majority of children with acute hepatitis were otherwise healthy.

Based on the opinion of pediatric hepatologists, hepatologists, and virologists who participated in the working group and multidisciplinary meetings, the cases reported through the reporting system did not represent an unusual event in France.

Data on emergency department visits for hepatitis of unknown etiology from the OSCOUR® network have remained stable since the beginning of 2022 and do not indicate an excess of cases. Analysis of PMSI data for the first 26 weeks of 2022 shows a number of hospital stays comparable to the average observed over the same period from 2012 to 2021, regardless of the age group considered.

Internationally:

  • As of September 29, 2022,

    • 555 cases of acute hepatitis of unknown origin in children aged 16 or younger had been reported by 20 countries in the European Union and the European Economic Area (277 cases) and the United Kingdom (278 cases).

    • 44 new cases were reported compared to the August 25 update, with a significant and ongoing decrease in the number of reported cases.

  • As of July 8, 2022, 1,010 probable cases have been reported by 35 countries across five WHO regions, though it is not possible to determine whether these represent an excess of cases or whether they reflect the usual number of cases in most countries. In the United States, reported cases do not appear to represent an excess compared to previous years.

System for monitoring and reporting suspected cases of acute pediatric hepatitis in France

To track the evolution of reported suspected cases across the country, Santé publique France has adapted its surveillance system. A specific reporting system for suspected cases, in addition to syndromic surveillance, was established as soon as the first cases were reported in the United Kingdom. Since October 1, 2022, this system has been suspended but can be reactivated if the situation changes. Currently, case surveillance relies on emergency department visit data and hospitalization data to detect any unusual events.

Step 1: Establishment of a specific reporting system for possible cases and syndromic surveillance

The system for reporting and investigating possible cases relied on a network of clinicians and laboratories, including pediatric intensive care units. Its objective was to detect any potential signal within the country similar to that observed in the United Kingdom.
A case definition was developed in collaboration with pediatric hepatologists and virologists from the three National Reference Centers involved. It pertained solely to the epidemiological investigation of the ongoing international alert and in no way altered the diagnostic, clinical, and therapeutic management of children presenting with acute hepatitis by medical teams.

In addition, Santé publique France regularly analyzed:

  • data on emergency department visits from the OSCOUR® network for a selection of diagnostic codes consistent with acute hepatitis of unknown etiology (excluding, in particular, viral hepatitis A through E) in children under 18 years of age, in order to identify any unusual increase in such cases over the recent period;

  • hospitalization data (PMSI) to detect any potential increase in the number of hospital stays consistent with acute hepatitis of unknown origin in children under 18 years of age.

Step 2: Scaling back the surveillance system

The dedicated reporting system established in May 2022 by Santé publique France and its partners is suspended effective October 1, 2022, given:

  • the absence of an excess of cases identified since the beginning of 2022 in France, both in emergency department visit data from the OSCOUR® network and in hospitalization data,

  • the lack of reports from pediatric hepatologists at French liver transplant centers regarding the number of severe hepatitis cases affecting children hospitalized in these centers or regarding any specific clinical presentations,

  • the very low number of reported cases with demographic, clinical, and microbiological characteristics different from those reported by the United Kingdom and appearing similar to the characteristics of patients typically seen in pediatric hepatology departments,

  • the significant decrease in the number of cases reported by the United Kingdom since June 2022.

This system can be easily and quickly reactivated if necessary. To this end, links with pediatric hepatology partners, hepatologists, and virologists will be maintained to detect any unusual signals that might suggest an event similar to that observed in the United Kingdom.
Monitoring of this event will now be based on regular analyses of emergency department visit data from the OSCOUR® network and hospitalization data (PMSI) to detect as early as possible any potential increase in emergency department visits for acute hepatitis (excluding viral hepatitis A through E) among children.

To date, the causes of the excess cases and the etiology of the cases described in the United Kingdom have not been definitively determined, and the number of cases has declined sharply in recent months. Santé publique France is in contact with its international partners, notably the ECDC and the WHO, to stay informed about the monitoring of this signal, the situation in the United Kingdom, and the identification of a cause.