Multi-country – acute and severe hepatitis of unknown origin in children

Please note that this outbreak news has been revised to correct the definition of a working state of the World Health Organization published on April 23, 2022.

outbreak at a glance:

Since news of the WHO outbreak of acute idiopathic hepatitis – United Kingdom of Great Britain and Northern Ireland was published on 15 April 2022, there have been further reports of cases of acute idiopathic hepatitis among young children. It is not yet clear whether there is an increase in hepatitis cases, or an increase in awareness of hepatitis cases that are occurring at the expected rate but are undetected. While adenoviruses are a possible hypothesis, investigations are underway regarding the causative agent.

Overview of the outbreak

As of 21 April 2022, at least 169 cases of acute hepatitis of unknown origin have been reported from 11 countries in the WHO European Region and one country in the WHO Region of the Americas (Fig. 1). Cases have been reported in the United Kingdom of Great Britain and Northern Ireland (UK) (114), Spain (13), Israel (12), the USA (9), Denmark (6), Ireland (<5), the Netherlands (4 ), Italy (4), Norway (2), France (2), Romania (1), and Belgium (1).

Figure 1. Distribution of cases of severe acute hepatitis of unknown origin by country, as of April 23, 2022.

The ages of the cases ranged from 1 month to 16 years. Seventeen children (about 10%) required a liver transplant; At least one death has been reported.

The clinical syndrome among the cases identified is acute hepatitis (hepatitis) with marked elevation of liver enzymes. Several cases have reported gastrointestinal symptoms including abdominal pain, diarrhea, and vomiting preceding onset with severe acute hepatitis, increased levels of liver enzymes (aspartate transaminase (AST) or alanine aminotransaminase (ALT) greater than 500 IU/L) and jaundice. Most of the cases did not have a fever. The common viruses that cause acute viral hepatitis (hepatitis A, B, C, D, and E viruses) were not detected in any of these cases. No international travel or links to other countries were identified based on currently available information as factors.

Adenovirus was detected in at least 74 cases, and among the number of cases with information on molecular testing, 18 were identified as type F 41. SARS-CoV-2 was identified in 20 of the cases tested. Moreover, 19 co-infected with SARS-CoV-2 and adenovirus were detected.

The United Kingdom, where the majority of cases have been reported to date, recently noted a significant increase in adenovirus infection in the community (particularly detected in stool samples in children) after lower circulating levels earlier in the COVID-19 pandemic. The Netherlands also reported a simultaneous increase in the circulation of community adenovirus.

However, due to improved lab testing for adenovirus, this could represent the identification of an existing rare result occurring at previously undetected levels that are now being recognized due to increased testing.

public health response

Further investigations are underway in countries that have identified cases and include more detailed clinical and exposure history, toxicology testing (ie testing for environmental and food toxicity), and additional viral/microbiological testing. Affected countries have also initiated enhanced surveillance activities.

The World Health Organization and the European Center for Disease Control and Prevention support countries in ongoing investigations and gathering information from countries that have reported cases. All available information is further disseminated by countries through hepatitis networks and clinical organizations such as the European Association for the Study of the Liver, the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPEGAN).

For cases in Europe, a joint WHO/CDC data collection will be established using the European Surveillance System (TESSy).

Guidance from the UK’s Health Security Agency has been issued to affected countries to support a thorough investigation of suspected cases.

WHO risk assessment

The United Kingdom reported for the first time an unexpectedly large increase in cases of severe acute hepatitis of unknown origin in young children who were generally healthy. An unexpected increase in such cases has been reported by several other countries – notably Ireland and the Netherlands.

While adenoviruses are currently one hypothesis as the underlying cause, they do not fully explain the severity of the clinical picture. Infection with type 41 adenovirus, the type of adenovirus involved, has not previously been associated with such a clinical presentation. Adenoviruses are common pathogens that usually cause self-limited infections. It spreads from person to person and mostly causes respiratory diseases, but depending on the type, it can also cause other diseases such as gastroenteritis (inflammation of the stomach or intestines), conjunctivitis (pink eye) and cystitis (bladder infection). There are more than 50 types of immunologically distinct adenovirus that can cause infection in humans. Type 41 adenoviruses usually present with diarrhea, vomiting, and fever, often with respiratory symptoms. Although there have been reports of cases of hepatitis in immunocompromised children with adenovirus infection, type 41 adenovirus is not known to be a cause of hepatitis in healthy children.

Factors such as increased susceptibility to infection among young children following a reduced level of adenovirus circulation during the COVID-19 pandemic, and the possible emergence of a new adenovirus, as well as SARS-CoV-2 co-infection, need further investigation. Hypotheses regarding the side effects of COVID-19 vaccines are not currently supported because the vast majority of infected children have not received the COVID-19 vaccination. Other infectious and non-infectious explanations for full risk assessment and management should be excluded.

With continued new notifications of cases that have emerged recently, at least in the UK, combined with more intensive case-finding, it is very likely that more cases will be discovered before the cause can be confirmed and more specific control and prevention measures can be implemented.

The World Health Organization is monitoring the situation closely and working with health authorities in the UK, other Member States and partners.

WHO advice

More work is needed to identify additional cases, both in currently affected countries and elsewhere. The priority is to identify the cause of these cases to further improve control and prevention measures. Common prevention measures against adenovirus and other common infections include regular hand washing and respiratory hygiene.

Member States are strongly encouraged to identify, investigate and report potential cases that fit the case definition1. Epidemiological information and risk factors should be collected and submitted by Member States to WHO and partner agencies through agreed reporting mechanisms. Any epidemiological links between or between cases may provide clues to tracing the source of the disease. Temporal and geographic information on cases, as well as close contacts of potential risk factors, should be reviewed.

WHO recommends blood testing (with preliminary anecdotal experience that whole blood is more sensitive than serum) and serum, urine, stool and respiratory samples, as well as liver biopsy samples (when available), with further virus characterization including sequencing. Other infectious and non-infectious causes should be thoroughly investigated.

The World Health Organization is not recommending any restrictions on travel and/or trade with the United Kingdom, or any other country in which cases are being identified, based on the information currently available.

1WHO business case definition:

  • Certain: Not available at the moment
  • Possible: a person with acute hepatitis (no hepA-E*) with serum transaminase >500 IU/L (AST or ALT), for those 16 years of age and younger, since October 1, 2021
  • Associated with EpiA person with acute hepatitis (not hepA-E*) Of any age is in close contact with a potential case, since October 1, 2021.

    *If results of hepatitis AE serum are expected, but other criteria are met, they may be reported and will be classified as ‘classification pending’. Cases with other explanations for their clinical presentation are ignored.

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