Raising cases of acute hepatitis: what are the risks

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Since the first alert launched by the United Kingdom (UK) on 5 April 2022, probable cases of hepatitis of unknown aetiology in children have been reported from several countries worldwide. It is not yet clear whether the cases identified following the alert are part of a true increase compared to the baseline rate of hepatitis of unknown aetiology in children.

Possible causes

Are there other possible causes? It has been suggested that the severity of the hepatitis is a result of the immune system working incorrectly – either too strongly or not strongly enough. Social distancing during the pandemic has reduced the transmission of a whole range of diseases, and a lack of exposure to them may have left some children unprepared for infections that normally wouldn’t cause a problem.

Equally, the lack of exposure to dirt as a result of handwashing, sterilising surfaces and other hygiene measures may have predisposed children to over-reactive immune responses (as has been suggested for allergic diseases), and the hepatitis may be caused by the immune response rather than a virus. Finally, and not surprisingly, it’s been suggested that previous COVID infections may have predisposed children to hepatitis.

All of these are no more than theories at the moment, and the available data is insufficient to prioritise any of them or to use them to suggest control measures. Fortunately, the incidence is still extremely low, and until there is better data parents should probably concentrate more on keeping an eye out for any symptoms in their children than on reducing their exposure to dogs.

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 (Figure 1). Cases have been reported in the United Kingdom of Great Britain and Northern Ireland (the United Kingdom) (114), Spain (13), Israel (12), the United States of America (9), Denmark (6), Ireland (<5), The Netherlands (4), Italy (4), Norway (2), France (2), Romania (1), and Belgium (1) Common prevention measures for adenovirus and other common infections involve regular hand washing and respiratory hygiene.

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

Cases are aged 1 month to 16 years old. Seventeen children (approximately 10%) have required liver transplantation; at least one death has been reported.

The clinical syndrome among identified cases is acute hepatitis (liver inflammation) with markedly elevated liver enzymes. Many cases reported gastrointestinal symptoms including abdominal pain, diarrhoea and vomiting preceding presentation with severe acute hepatitis, and increased levels of liver enzymes (aspartate transaminase (AST) or alanine aminotransaminase (ALT) greater the 500 IU/L) and jaundice. Most cases did not have a fever. The common viruses that cause acute viral hepatitis (hepatitis viruses A, B, C, D and E) have not been detected in any of these cases.  International travel or links to other countries based on the currently available information have not been identified as factors.

Adenovirus has been detected in at least 74 cases, and of the number of cases with information on molecular testing, 18 have been identified as F type 41. SARS-CoV-2 was identified in 20 cases of those that were tested. Furthermore, 19 were detected with a SARS-CoV-2 and adenovirus co-infection.

The United Kingdom, where the majority of cases have been reported to date, has recently observed a significant increase in adenovirus infections in the community (particularly detected in faecal samples in children) following low levels of circulation earlier in the COVID-19 pandemic. The Netherlands also reported concurrent increasing community adenovirus circulation.

Nevertheless, due to enhanced laboratory testing for adenovirus, this could represent the identification of an existing rare outcome occurring at levels not previously detected that is now being recognized due to increased testing.

Public health response

Further investigations are ongoing in countries that have identified cases and include more detailed clinical and exposure histories, toxicology testing (i.e. environmental and food toxicity testing), and additional virological/microbiological tests. Affected countries have also initiated enhanced surveillance activities.

WHO and ECDC are supporting countries with the ongoing investigations and collecting information from the countries reporting cases. All available information is further disseminated by countries through their Hepatitis Networks and clinical organisations such as the European Association for the Study of the Liver, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

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

Guidance derived by the United Kingdom Health Security Agency has been issued to affected countries to support a thorough investigation of suspected cases.

WHO risk assessment

The United Kingdom first reported an unexpected significant increase in cases of severe acute hepatitis of unknown origin in young, generally previously healthy children. An unexpected increase of such cases has now been reported by several other countries – notably Ireland and the Netherlands.

While adenovirus is currently one hypothesis as the underlying cause, it does not fully explain the severity of the clinical picture. Infection with adenovirus type 41, the implicated adenovirus type, has not previously been linked to such a clinical presentation. Adenoviruses are common pathogens that usually cause self-limited infections. They spread from person-to-person and most commonly cause respiratory illness, but depending on the type, can also cause other illnesses 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 adenoviruses that can cause infections in humans. Adenovirus type 41 typically presents as diarrhea, vomiting, and fever, often accompanied by respiratory symptoms. While there have been case reports of hepatitis in immunocompromised children with adenovirus infection, adenovirus type 41 is not known to be a cause of hepatitis in otherwise healthy children.

Factors such as increased susceptibility amongst young children following a lower level of circulation of adenovirus during the COVID-19 pandemic, the potential emergence of a novel adenovirus, as well as SARS-CoV-2 co-infection, need to be further investigated. Hypotheses related to side effects from the COVID-19 vaccines are currently not supported as the vast majority of affected children did not receive COVID-19 vaccination. Other infectious and non-infectious explanations need to be excluded to fully assess and manage the risk.

With continued new notifications of recent onset cases, at least in the United Kingdom, together with more extensive case searching, it is very likely that more cases will be detected before the cause can be confirmed and more specific control and prevention measures can be implemented.

WHO is closely monitoring the situation and working with the United Kingdom health authorities, other Member States and partners.

WHO advice

Further work is required to identify additional cases, both in currently affected countries and elsewhere. The priority is to determine the cause of these cases to further refine control and prevention actions. Common prevention measures for adenovirus and other common infections involve regular hand washing and respiratory hygiene.

Member States are strongly encouraged to identify, investigate and report potential cases fitting the case definition1. Epidemiological and risk factor information should be collected and submitted by Member States to WHO and partner agencies through agreed reporting mechanisms. Any epidemiological links between or among the cases might provide clues for tracking the source of illness. Temporal and geographical information about the cases, as well as their close contacts should be reviewed for potential risk factors.

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

WHO does not recommend any restriction on travel and/or trade with the United Kingdom, or any other country where cases are identified, based on the currently available information.

1WHO working case definition:

  • Confirmed: N/A at present
  • Probable: A person presenting with an acute hepatitis (non hepA-E*) with serum transaminase >500 IU/L (AST or ALT), who is 16 years and younger, since 1 October 2021
  • Epi-linked: A person presenting with an acute hepatitis (non hepA-E*) of any age who is a close contact of a probable case, since 1 October 2021. 
  • Since the first alert launched by the United Kingdom (UK) on 5 April 2022, probable cases of hepatitis of unknown aetiology in children have been reported from several countries worldwide. It is not yet clear whether the cases identified following the alert are part of a true increase compared to the baseline rate of hepatitis of unknown aetiology in children.

    The aetiology and pathogenetic mechanisms of disease are still under investigation. A possible association with current adenovirus infection has been found in cases in the UK in particular but other hypotheses and possible co-factors are under investigation. Most cases continue to be reported as sporadic un-linked cases.

    This report presents an update of probable cases identified in the European Union/European Economic Area (EU/EEA) and worldwide. Whereas cases detected in the EU/EEA have been reported according to the ECDC/WHO case definition, worldwide cases are collected through screening of official websites and media sources and therefore different case definitions could have been used.

    Case definition used in EU/EEA:

    • Confirmed: N/A
    • Probable: A person presenting with an acute hepatitis (non-hepatitis viruses A, B, C, D and E*) with aspartate transaminase (AST) or alanine transaminase (ALT) over 500 IU/L, who is 16 years old or younger, since 1 October 2021.
    • Epi-linked: A person presenting with an acute hepatitis (non-hepatitis viruses A, B, C, D and E*) of any age who is a close contact of a probable case since 1 October 2021.

    Cases of hepatitis with known aetiology such those due to specific infectious diseases, drug toxicity, and metabolic hereditary, or autoimmune disorders should not be reported under this protocol.
    In EU/EEA countries, approximately 105 cases have been identified in 13 EU/EEA countries as of 10 May 2022.

    Table 1. Number of identified cases by country, EU/EEA, 10 May 2022

    Country Cases
    Austria 2
    Belgium 3
    Cyprus 2
    Denmark 6
    France 2
    Ireland Fewer than 5
    Italy 35
    Netherlands 6
    Norway 4
    Poland 1
    Portugal 8
    Spain 22
    Sweden 9
    Total Between 102 and 106

    Figure 1. Geographical distribution of cases in EU/EEA, 11 May 2022

    Geographical distribution of cases in EU/EEA, 11 May 2022

    Worldwide update

    United Kingdom: As of 3 May 2022, the UKHSA has identified a total of 163 children, aged under 16 years, with acute hepatitis of unknown aetiology. Of these cases, 11 children have received a liver transplant. A second detailed technical briefing on the investigations among the UK cases was published by the UKHSA on 6 May 2022.

    Outside of EU/EEA and the United Kingdom: as of 10 May 2022, there are at least 181 cases of acute hepatitis among children. Cases have been reported by Argentina [8], Brazil [16], Canada [7], Costa Rica [2], Indonesia [15], Israel [12], Japan [7], Panama [1], Palestine* [1], Serbia [1], Singapore [1], South Korea [1] and the United States [at least 109].

    The total number of cases reported worldwide is approximately 450, including 11 deaths reported from Indonesia[5], Palestine [1], and the United States [5].

    On 3 May 2022, the media quoting public health authorities reported a death of an eight-year-old child with acute hepatitis of unknown aetiology in Palestine*. It is currently unclear whether this is the same child who was diagnosed in the previous week. Confirmation of this case is pending.

    *This designation shall not be construed as recognition of a State of Palestine and is without prejudice to the individual positions of the Member States on this issue.

    Actions: On 28 April 2022, ECDC published a rapid risk assessment. ECDC has established reporting of case-based data for cases of acute hepatitis of unknown aetiology in The European Surveillance System (TESSy). The reporting protocol is available here, and countries are strongly encouraged to report cases to TESSy. A separate report based on the data reported in TESSy will be published shortly.

    An EpiPulse item remains available to Member States (MS) to report updates on their investigations in order to inform and facilitate communication between MS and ECDC.

    ECDC will continue to monitor this event through its epidemic intelligence activities.

     

Recommendations for Clinicians

  • Clinicians should continue to follow standard practice for evaluating and managing patients with hepatitis of known and unknown etiology.
  • Clinicians are recommended to consider adenovirus testing for patients with hepatitis of unknown etiology and to report such cases to their state or jurisdictional public health authorities.
  • Because the potential relationship between adenovirus infection and hepatitis is still under investigation, clinicians should consider collecting the following specimen types if available from pediatric patients with hepatitis of unknown cause for adenovirus detection:
    • Blood specimen collected in Ethylenediaminetetraacetic Acid (EDTA) (whole blood, plasma, or serum); whole blood is preferred to plasma and serum)
    • Respiratory specimen (nasopharyngeal swab, sputum, or bronchioalveolar lavage [BAL])
    • Stool specimen or rectal swab; a stool specimen is preferred to a rectal swab
    • Liver tissue, if a biopsy was clinically indicated, or if tissue from native liver explant or autopsy is available:
      • Formalin-fixed, paraffin embedded (FFPE) liver tissue
      • Fresh liver tissue, frozen on dry ice or liquid nitrogen immediately or as soon as possible, and stored at ≤ -70°C
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