No 15/17a - 2022

International outbreak of hepatitis of unknown cause

Based on various recently detected hepatitis (inflammation of the liver) cases of unknown cause among children in various countries in Europe, the US and Israel, we here provide a short update and attention points for healthcare workers.

In late March 2022, a cluster of hepatitis cases of unknown cause was identified in Scotland. The cluster counted five children aged 3-5 years who had been admitted to hospital in the three preceding weeks. All of the children tested negative to the viruses that typically cause hepatitis (A-E), and no other obvious causes of their hepatitis were found. Normally approx. four annual cases of this type are detected in Scotland. Around the same time, a similar cluster of hepatitis cases of unknown cause was detected in England. A total of 114 cases were detected in Great Britain (England and Scotland) as from 23 April through tracing based on a case definition (working definition of disease cases) delimited as cases of acute hepatitis recorded as from 1 January 2022 with tranaminase values > 500 IU/L in children aged 10 years or younger, who had tested negative to hepatitis A-E virus and with no other known cause.

As from 1 January 2022, a total of eight EU countries, including Denmark, have observed between one and 11 similar cases of hepatitis of unknown cause in children; a total of 29 cases, and in Ireland < 5 cases, were detected (precise figures not given). In Denmark, a total of six cases have been recorded in the age from two to 14 years of age since 1 January 2022. Outside of the EU, nine cases have been recorded in the US and 12 cases in Israel. The occurrence figures for these countries were provided by the ECDC and Public Health England at the ECCMID conference in Lisbon on 25 April 2022.

A total of 16 children have received a liver transplant, ten in Great Britain, three in the Netherlands, one in Spain and two in the US. The overwhelming majority of the children were healthy until being diagnosed with hepatitis.

In Great Britain, where most cases have been observed, 50% of the cases were detected in the period from 21 March to 10 April, but cases have been recorded in all weeks since 1 January 2022.

Symptoms

The symptoms of the English cases, where symptoms were reported systematically, are in line with known hepatitis symptoms, including icterus (jaundice), nausea and vomiting, diarrhoea, abdominal pain, discoloured stools, fatigue, dizziness and fever, and in a limited number of cases airway symptoms, rash, conjunctivitis (eye inflammation) and bloody stools. Icterus and the mentioned gastrointestinal symptoms are the most frequently observed symptoms in these patients.

In England, the cases have been scattered across the country, and no connection has been established between the cases. Only few of the cases have received COVID-19 vaccination, as most of the children were too young for vaccination. Furthermore, no link to SARS-CoV-2 infection was established.

Ongoing studies and possible causes of the outbreak

Currently, a range of epidemiological, microbiological and toxicological studies are being conducted of the cases, primarily in Great Britain, but also in the other countries where cases have been recorded. The countries collaborate with the WHO and the ECDC in this respect.

The main questions are to which degree the cases represent an outbreak, which countries are comprised and what the cause or causes of the outbreak are.

There is barely any doubt that the cases observed in Great Britain constitute an outbreak, but this is less obvious for the remaining EU countries, including Denmark. Thus, markedly fewer known cases have been recorded in each of these countries than in Great Britain, and every year a number of similar hepatitis cases of unknown cause are recorded in children < 10 years. To take an example, Denmark records an average of two similar cases annually.

With respect to possible causes, preliminary studies mainly based in Great Britain have generated the following working hypotheses, listed by descending probability (hypotheses presented by Public Health England at the ECCMID conference in Lisbon on 25 April 2022, and by Investigation into acute hepatitis of unknown aetiology in children in England Technical briefing):

1. A contributory cause that affects young children and renders a normal adenovirus infection more serious or triggers an abnormal immune response in the children. This might be enhanced susceptibility to adenovirus due to lacking previous exposure during the COVID-19 pandemic; a previous or concurrent infection with SARS-CoV-2 or another virus; or a toxin, a medicinal product or an environmental agent.
2. A new adenovirus variant with or without a contributory factor, as stated above.
3. A toxin, a medicinal product or an environmental agent.
4. A new pathogen, which either acts independently or in conjunction with another infection.
5. A new variant of SARS-CoV-2.

Precautions

It is important to stress that the current number of cases recorded in Denmark and other countries outside of Great Britain is very low and that similar cases are recorded every year. Furthermore, the cause remains unknown, and therefore special precautions are not needed. As always, it is important to be attentive to a child’s symptoms, which in these cases typically present as icterus, general symptoms and gastrointestinal symptoms, and - as normally - engage in diagnostic work up to establish the cause. Admitted children who are suspected of being comprised by the outbreak are handled in accordance with current guidelines on children with increase in transaminases and may be conferred with the highly specialised paediatric pathology function at the Copenhagen University Hospital (Rigshospitalet), Odense University Hospital or Aarhus University Hospital, Skejby.

The situation is being monitored closely

The situation is monitored closely, nationally as well as internationally. In Denmark, extended monitoring was established in the form of mandatory notification by phone to the Danish Patient Safety Authority of hepatitis of unknown cause and via close collaboration between Danish paediatricians and paediatric departments, the Danish Health Authority, the Danish Patient Safety Authority and Statens Serum Institut.

Notification

On 12 April the Danish Health Authority informed paediatric departments that disease cases like those described in Great Britain must be notified by phone to the Danish Patient Safety Authority and in writing to the Danish Patient Safety Authority and Statens Serum Institut to facilitate monitoring and epidemiological investigation of the possible outbreak. Notification is made in pursuance of Section 7 of Executive Order on Notification (on clusters of inexplicable disease cases that may be caused by a biological agent, but where such agent has not necessarily been detected).

Notification:

• The cases covered by mandatory notification include children below 16 years of age:
  o with significant liver affection (guiding ALAT/ASAT > 500 IU/L)
  o AND negative hepatitis A-E diagnostics
  o AND no other known aetiology
• The case is notified by phone to the Danish Patient Safety Authority in the area where the patient resides.
• Contact information for the Danish Patient Safety Authority: +45 72227450 (Capital Region of Denmark and Region Zealand), 72227950 (Region of Southern Denmark) and 72227970 (North Denmark Region and Central Denmark Region). Outside of normal daily opening hours, the preparedness service of the Danish Patient Safety Authority is contacted (70220268 East of Storebælt, 70220269 West of Storebælt).
• Subsequently, the case is notified in writing to the Danish Patient Safety Authority, either by using the electronic notification system in the SEI2 (currently not available in the Region of South Denmark, but the SSI can provide access as needed) or on Form 1515, which is submitted by surface mail.
• For written notifications, the diagnosis is stated as “Suspicion of clustering of serious disease cases of unknown cause”.

(A. Koch, L. Müller, R. Legarth, P.H. Andersen, P. Valentiner-Branth, L. Espenhain, V. Vorobieva Jensen, Statens Serum Institut, M. Hørby Jørgensen, Copenhagen University Hospital (Rigshospitalet), M. Aabye, G. Ertner, Danish Health Authority, A. Hempel-Jørgensen, Danish Patient Safety Authority)