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The recent outbreak of acute severe hepatitis in children of unknown origin – what is known so far

  • Eberhard Lurz
    Correspondence
    Corresponding author. Address: Dr. von Hauner University Children Hospital, LMU Munich, Lindwurmstrasse 4, 80337 Munich, Germany; Tel.: +49 89 4400519060.
    Affiliations
    University Hospital, LMU Munich, Department of Pediatrics, Munich, Germany

    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany
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  • Dominic Lenz
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Hospital Heidelberg, Centre for Pediatric and Adolescent Medicine, Heidelberg, Germany
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  • Philip Bufler
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Medicine Charité, Department of Pediatrics, Berlin, Germany
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  • Alexander Fichtner
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Hospital Heidelberg, Centre for Pediatric and Adolescent Medicine, Heidelberg, Germany
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  • Stephan Henning
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Medicine Charité, Department of Pediatrics, Berlin, Germany
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  • Martin Jankofsky
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Medical Center Hamburg-Eppendorf, Department of Pediatrics, Hamburg, Germany
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  • Simone Kathemann
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Medicine Essen, University Children’s Hospital, Pediatric Gastroenterology, Hepatology and Transplant Medicine, Essen, Germany
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  • Michael Melter
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Hospital Regensburg, KUNO University Children's Hospital, Regensburg, Germany
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  • Jun Oh
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Medical Center Hamburg-Eppendorf, Department of Pediatrics, Hamburg, Germany
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  • Eva Doreen Pfister
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    Hannover Medical School, Clinic for Pediatric Kidney, Liver, and Metabolic Diseases, Hannover, Germany
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  • Ekkehard Sturm
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    Eberhard Karls University Tubingen, Pediatric Gastroenterology and Hepatology, University Children's Hospital, Tübingen, Germany
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  • Birgit Knoppke
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Hospital Regensburg, KUNO University Children's Hospital, Regensburg, Germany
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  • Elke Lainka
    Affiliations
    Working Group Pediatric Liver Transplantation of the German Speaking Society of Pediatric Gastroenterology, Hepatology and Nutrition (GPGE), Germany

    University Medicine Essen, University Children’s Hospital, Pediatric Gastroenterology, Hepatology and Transplant Medicine, Essen, Germany
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      Linked Article

      • The recent outbreak of acute severe hepatitis in children of unknown origin – what is known so far
        Journal of HepatologyVol. 77Issue 1
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          At the beginning of April 2022, 10 cases of severe acute hepatitis of unknown origin in children <10 years of age were reported across central Scotland. Since then, case numbers have increased rapidly, with 191 probable cases identified across Europe, the United States of America, Israel and Japan. Until now, 17 children required liver transplantation and 1 died. Accordingly, the Centers for Disease Control and Prevention and the European Centre for Diseases Prevention and Control have both issued a warning on a hepatitis of unknown origin in children.
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      To the Editor:
      We have read with great interest the manuscript by Mücke and Zeuzem accepted for publication in the Journal of Hepatology in May 2022. The authors discuss the current concern over an increasing number of children presenting with a so-called severe non-A-E hepatitis, a finding initially reported from the United Kingdom across central Scotland (World Health Organization [WHO] Disease Outbreak News 15th Apr 2022) and subsequently from 15 other countries.
      • Mücke M.M.
      • Zeuzem S.
      The recent outbreak of acute severe hepatitis in children of unknown origin – what is known so far.
      The authors discuss different potential epidemiologic reasons for the occurrence, as well as one particular concern, also raised by the authorities, which is the potential association of human adenovirus (hADV) infection with these cases, more precisely an infection with a specific hADV serotype F41.
      More recently, on May 11th, the Centers for Disease Control and Prevention (CDC) updated the North American experience, where 109 children were reported having unknown hepatitis, out of whom more than half tested positive for adenovirus, 14% required liver transplantation (LT) and 5 died.
      On May 12th, a group of representatives for the European reference network (ERN) RARE-LIVER published the data of a short survey which was sent to all ERN members with a specialized service in pediatric hepatology, summarizing a total of 64 cases of acute hepatitis recorded since January 2022 from 34 centers and 22 countries throughout Europe and Israel. In 38 (60%) of these cases a plausible cause for the acute hepatitis was identified. Four might have been related to a SARS-CoV-2 infection (3 had active COVID-19) and in 9, different viruses including adenovirus (n = 4), were detected. Four of the children required LT and 4 (3 before LT, 1 after LT) died.
      • de Kleine R.H.
      • Lexmond W.S.
      • Buescher G.
      • Sturm E.
      • Kelly D.
      • Lohse A.W.
      • et al.
      Severe acute hepatitis and acute liver failure of unknown origin in children : a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel.
      Since devastating courses of severe acute hepatitis, with death or the need for LT, are indeed highly worrying, and demand further precise work up, a group of German pediatric hepatologists and representatives of the German pediatric LT centers discussed these reports at the annual meeting of the German speaking Association (Germany, Austria, Swiss) of pediatric Gastroenterology, Hepatology and Nutrition (GPGE) on May 13th in Rostock, Germany. The expert consensus concluded that it is currently too early to describe a new ‘wave’ of severe cases with non-A-E hepatitis. The current cluster resembles the expected amount and distribution of children presenting with acute severe hepatitis or acute liver failure.
      • de Kleine R.H.
      • Lexmond W.S.
      • Buescher G.
      • Sturm E.
      • Kelly D.
      • Lohse A.W.
      • et al.
      Severe acute hepatitis and acute liver failure of unknown origin in children : a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel.
      Discussion regarding an hADV infection causing the presented cases was particularly highly debated, as thus far no case of ADV infiltration of the liver has been reported. It is expected that a change in societal behavior, and less exposure to pathogens due to various measures during the SARS-CoV-2 pandemic, might cause changes in established transmission patterns of viral infections as well as individual immune responses. This hypothesis is supported by the current decrease of influenza A infections,
      • Leng M.
      A trend for decrease of influenza infections in children during the first wave of COVID-19 observed in a Chinese hospital.
      or by a timely shift of respiratory syncytial virus (RSV) infections in the last few years.
      • Williams H.
      Epidemic jaundice in New York State, 1921-1922.
      An overall higher current incidence of classic hADV infections in children presenting with respiratory symptoms was also reported. For comparison, the elevated number of cases of severe hepatitis and gastrointestinal symptoms after the 1918 flu pandemic was discussed.
      • Toelen J.
      • Ritz N.
      • de Winter J.P.
      Changes in pediatric infections during the COVID-19 pandemic: 'a quarantrend for coronials'?.
      Of concern is a potential association of the reported cases with a previous SARS-CoV-2 infection which might have caused hepatitis leading to i) a higher susceptibility of the liver and ii) an overwhelming inflammation in the setting of any other viral infection, which can also be seen in so-called seronegative autoimmune hepatitis or hepatitis-associated aplastic anemia.
      We endorse the conclusion of Mücke and Zeuzem, and support activities by health agencies such as the WHO, the European Centre for Disease Prevention and Control, and local authorities, to collect more and precise data in a timely fashion.
      • Mücke M.M.
      • Zeuzem S.
      The recent outbreak of acute severe hepatitis in children of unknown origin – what is known so far.
      • de Kleine R.H.
      • Lexmond W.S.
      • Buescher G.
      • Sturm E.
      • Kelly D.
      • Lohse A.W.
      • et al.
      Severe acute hepatitis and acute liver failure of unknown origin in children : a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel.
      ,
      World Health Organization
      Disease Outbreak News; Acute hepatitis of unknown aetiology - the United Kingdom of Great Britain and Northern Ireland.
      European Centre for Disease Prevention and Control
      TESSy - the European surveillance: hepatitis of unknown origin reporting protocol.

      Robert Koch Institut - Fälle akuter Hepatitis unklarer Ätiologie (non A bis E) bei Kindern. Available at: https://www.rki.de/DE/Content/Infekt/Ausbrueche/aktuell/Hepatitis-unklarer-Aetiologie.html.

      However, we advise caution in making early and/or premature conclusions concerning this sensitive matter, since to date, and to the best of our knowledge (at least in Germany and within the ERN community), there has been no substantial increase in severe pediatric acute hepatitis and/or acute liver failure of unknown origin.
      To put these cases within the correct clinical context, we therefore strongly suggest using established pediatric infrastructures provided by, for example, the ERN RARE-LIVER and other expert bodies, such as national and international associations of pediatric hepatologists (GPGE, the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN, NASPGHAN]), the members of which have first-hand experience of this issue.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors' contributions

      EL drafted, wrote and approved this letter; DL, BK, EL reviewed, added content, wrote and approved this letter; BP, AF, SH, MJ, SK, MM, JO, EP & ES critically reviewed and approved this letter.

      Conflict of interest

      There is no conflict of interest to declare.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Mücke M.M.
        • Zeuzem S.
        The recent outbreak of acute severe hepatitis in children of unknown origin – what is known so far.
        J Hepatol. 2022 Jul; 77 (Epub 2022 May 6): 237-242https://doi.org/10.1016/j.jhep.2022.05.001
      1. (Version 1.0. GOV-12076)UK Health Security Agency Technical briefing: investigation into acute hepatitis of unknown aetiology in children in England. 25 April 2022 (Available at:)
      2. (Distributed via the CDC Health Alert Network)Updated recommendations for adenovirus testing and reporting of children with acute hepatitis of unknown etiology. May 11, 2022 (12:15 PM ET CDCHAN-00465 Available at:)
        • de Kleine R.H.
        • Lexmond W.S.
        • Buescher G.
        • Sturm E.
        • Kelly D.
        • Lohse A.W.
        • et al.
        Severe acute hepatitis and acute liver failure of unknown origin in children : a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel.
        Euro Surveill. April 2022; 2022 (pii=2200369): 27
        • Leng M.
        A trend for decrease of influenza infections in children during the first wave of COVID-19 observed in a Chinese hospital.
        J Lab Med. 2021; 45: 241-243https://doi.org/10.1515/labmed-2021-0069
        • Williams H.
        Epidemic jaundice in New York State, 1921-1922.
        JAMA. 1923; 80: 532-534https://doi.org/10.1001/jama.1923.02640350014007#
        • Toelen J.
        • Ritz N.
        • de Winter J.P.
        Changes in pediatric infections during the COVID-19 pandemic: 'a quarantrend for coronials'?.
        Eur J Pediatr. 2021; 180: 1965-1967
        • World Health Organization
        Disease Outbreak News; Acute hepatitis of unknown aetiology - the United Kingdom of Great Britain and Northern Ireland.
        15 April 2022 (Available at:)
        • European Centre for Disease Prevention and Control
        TESSy - the European surveillance: hepatitis of unknown origin reporting protocol.
        2022 (Available at:)
      3. Robert Koch Institut - Fälle akuter Hepatitis unklarer Ätiologie (non A bis E) bei Kindern. Available at: https://www.rki.de/DE/Content/Infekt/Ausbrueche/aktuell/Hepatitis-unklarer-Aetiologie.html.