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The origin of severe hepatitis of unknown aetiology in children: SARS-CoV-2 or adenovirus?

  • Hang Yi
    Affiliations
    Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
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  • Yiwen Lin
    Affiliations
    Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
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  • Bin Lu
    Affiliations
    Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
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  • Yousheng Mao
    Correspondence
    Corresponding author. Address: Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
    Affiliations
    Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
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Published:September 02, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.032

      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:
      Since April 5, 2022, a mysterious severe acute hepatitis of unknown aetiology was reported in previously healthy children in multiple countries, starting in the UK, and spreading across the European area.
      European Center for Disease Prevention and Control
      Increase in severe acute hepatitis cases of unknown aaetiology in children – 28 April 2022.
      With great interest, we read an article introducing the recent hepatitis outbreak by Mücke et al. published in the Journal in May 2022 and were inspired by their hypotheses.
      • Mücke M.M.
      • Zeuzem S.
      The recent outbreak of acute severe hepatitis in children of unknown origin - what is known so far.
      Up to July 28, 2022, a total of 508 cases of acute hepatitis of unknown aetiology in children have been reported in the European region (geographic distribution shown in Fig. 1A).
      European Center for Disease Prevention and Control
      Joint ECDC-WHO regional office for Europe weekly hepatitis of unknown origin in children surveillance bulletin.
      These 508 cases were identified as probable cases, which was defined as a child aged 16 years and younger, presenting with an acute hepatitis (not caused by hepatitis A–E viruses) with serum transaminase >500 IU/L.
      World Health Organization
      Severe acute hepatitis of unknown aaetiology in children - multi-country.
      The outbreak of hepatitis has raised alert around the world including in China, the National Health Commission of which released nationwide guidelines on acute severe hepatitis of unknown aetiology in children on June 16, 2022.
      National Health Commission of the People's Republic of China
      Notice of the general office of the national health commission on printing and distributing guidelines for the diagnosis and treatment of severe acute hepatitis of unknown aetiology in children.
      Urgent identification of the cause and underlying mechanisms of the disease is crucial in order to enable appropriate clinical management.
      Figure thumbnail gr1
      Fig. 1Comparing the distribution of hepatitis cases and Omicron cases across Europe.
      (A) Geographic distribution of hepatitis cases in European region. (B) Cumulative incidence of Omicron cases among children (<15 years old) in relation to the detection of severe acute hepatitis of unknown aetiology among children. (Wilcoxon rank sum test, box plot measures the quartiles and median) (C) Correlation analysis of cumulative Omicron cases among children and hepatitis cases reported. (Spearman correlation analysis used. Each red dot represents one hepatitis-detected country).
      To investigate the potential link between infection with COVID-19 (Omicron variant) and severe hepatitis of unknown aetiology among children, Nishiura H and his colleagues
      • Nishiura H.
      • Jung S.M.
      • Hayashi K.
      High population burden of Omicron variant (B.1.1.529) is associated with the emergence of severe hepatitis of unknown aetiology in children.
      compared the absolute number of Omicron cumulative cases between the hepatitis-detected countries and hepatitis-undetected ones and they drew a conclusion that prior exposure to the Omicron variant (B.1.1.529) might be associated with an increased risk of severe hepatitis among children. However, the absolute number of cumulative Omicron cases is not a favourable indicator compared with cumulative incidence and more notably, the whole population cannot represent children, which biased their result. We collected the child-specific population data from the ECDC and performed an analysis of Omicron infection in children and its association with the emergence of severe hepatitis of unknown aetiology.
      In our analysis, there was no significant difference (Fig. 1B, p = 0.32) in the cumulative incidence of Omicron cases among children between hepatitis-detected countries and hepatitis-undetected ones. Then, we further analysed the association of cumulative Omicron cases among children and hepatitis cases reported in hepatitis-detected countries by conducting a Spearman correlation analysis. The results showed that there was a positive association between Omicron cases in children and hepatitis cases (Fig. 1C, r = 0.64, p = 5.9e-3). The results were consistent with an analysis two months ago
      • Yi H.
      • Lin Y.
      • Lu B.
      • Mao Y.
      Comment on “High population burden of Omicron variant (B.1.1.529) is associated with the emergence of severe hepatitis of unknown aetiology in children”.
      which proved that these results were time-independent and strengthened their validity.
      Laboratory investigations conducted by the UK Health Security Agency (UKHSA) found that adenovirus 41F was positive in 72% of the cases; and out of the 398 cases in European countries tested for adenovirus, 217 (54.5%) tested positive, so current hypotheses continue to focus on adenovirus as a potential aetiology.
      European Center for Disease Prevention and Control
      Joint ECDC-WHO regional office for Europe weekly hepatitis of unknown origin in children surveillance bulletin.
      ,
      • Cevik M.
      • Rasmussen A.L.
      • Bogoch I.I.
      • Kindrachuk J.
      Acute hepatitis of unknown origin in children.
      Moreover, though lacking positive liver histologic findings for adenoviral inclusion, a clinical study by Kelgeri et al. reported that biochemical tests and ultrasonographic results are consistent with a viral cause, and serum levels of adenovirus were significantly higher in the patients who progressed to liver failure than those who spontaneously recovered.
      • Kelgeri C.
      • Couper M.
      • Gupte G.L.
      • Brant A.
      • Patel M.
      • Johansen L.
      • et al.
      Clinical spectrum of children with acute hepatitis of unknown cause.
      ,
      • Karpen Saul J.
      Acute hepatitis in children in 2022 — human adenovirus 41?.
      However, adenovirus alone is rarely associated with severe hepatitis, so other factors that lead to abnormal susceptibility or host response may contribute to the severity of the disease. Contributing factors include lack of previous exposure due to quarantine during the SARS-CoV-2 pandemic, abnormal susceptibility caused by previous infection or co-infection with SARS-CoV-2 or other pathogens.
      • Cevik M.
      • Rasmussen A.L.
      • Bogoch I.I.
      • Kindrachuk J.
      Acute hepatitis of unknown origin in children.
      We speculated that the severe acute hepatitis was possibly induced by adenovirus, while SARS-CoV-2 acted as a cofactor and allowed adenovirus infection to progress more frequently to severe hepatitis. Our hypotheses are based on the following factors. Firstly, SARS-CoV-2 is probably not the main cause of hepatitis since there were no differences in incidence rates among children between the two country groups. Instead, SARS-CoV-2 might play a role in disease progression. Secondly, we believe the positive association between Omicron cases and hepatitis cases reported is possibly biased by the shared route of transmission of Omicron and adenovirus since these two types of viruses are mainly transmitted through the respiratory tract.
      Centers for Disease Control and Prevention
      CDC alerts providers to hepatitis cases of unknown origin.
      Thus, a potential positive relationship between adenovirus cases and Omicron cases exits in one country endowed with the similar public health and social measures. Thirdly, previous studies have reported a lower circulation of adenovirus due to the COVID-19 pandemic quarantine, and lack of exposure to adenovirus resulted in increased susceptibility among children, thus leading to the severity of this adenovirus outbreak.
      • Mücke M.M.
      • Zeuzem S.
      The recent outbreak of acute severe hepatitis in children of unknown origin - what is known so far.
      In addition, the UKHSA suggested that prior infection or co-infection with SARS-CoV-2 may have led to abnormal host responses or susceptibility to adenovirus infection.
      UK Health Security Agency
      ,
      The Lancet Infectious Diseases
      Explaining the unexplained hepatitis in children.
      The specific mechanism and the extent to which SARS-CoV-2 affects adenovirus infections resulting in severe acute hepatitis remains a mystery. In the future, much attention should be paid to this area to put an end to this severe hepatitis outbreak.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      Hang Yi, Yiwen Lin and Bin Lu were involved in conceptualizing, literature review, drafting of the letter and Yousheng Mao revised the letter for final submission. All authors approved the final version for submission and publication of the content.

      Data availability statement

      The present study used publicly available data from the ECDC (https://www.ecdc.europa.eu/en).

      Ethics approval statement

      The publicly available data were anonymous and ethical approval and patient consent statement can be waived.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • European Center for Disease Prevention and Control
        Increase in severe acute hepatitis cases of unknown aaetiology in children – 28 April 2022.
        2022 ([cited 2022 June 3])
        • 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: 237-242
        • European Center for Disease Prevention and Control
        Joint ECDC-WHO regional office for Europe weekly hepatitis of unknown origin in children surveillance bulletin.
        2022 ([cited 2022 July 29])
        • World Health Organization
        Severe acute hepatitis of unknown aaetiology in children - multi-country.
        2022 ([cited 2022 July 29])
        • National Health Commission of the People's Republic of China
        Notice of the general office of the national health commission on printing and distributing guidelines for the diagnosis and treatment of severe acute hepatitis of unknown aetiology in children.
        2022 ([cited 2022 July])
        • Nishiura H.
        • Jung S.M.
        • Hayashi K.
        High population burden of Omicron variant (B.1.1.529) is associated with the emergence of severe hepatitis of unknown aetiology in children.
        Int J Infect Dis. 2022 May 13; 122: 30-32
        • Yi H.
        • Lin Y.
        • Lu B.
        • Mao Y.
        Comment on “High population burden of Omicron variant (B.1.1.529) is associated with the emergence of severe hepatitis of unknown aetiology in children”.
        Int J Infect Dis. 2022 Sep; 122: 1007-1008
        • Cevik M.
        • Rasmussen A.L.
        • Bogoch I.I.
        • Kindrachuk J.
        Acute hepatitis of unknown origin in children.
        BMJ. 2022 May 17; 377: o1197
        • Kelgeri C.
        • Couper M.
        • Gupte G.L.
        • Brant A.
        • Patel M.
        • Johansen L.
        • et al.
        Clinical spectrum of children with acute hepatitis of unknown cause.
        New Engl J Med. 2022 Aug 18; 387: 611-619
        • Karpen Saul J.
        Acute hepatitis in children in 2022 — human adenovirus 41?.
        New Engl J Med. July 13, 2022; (NEJMe2208409)https://doi.org/10.1056/NEJMe2208409
        • Centers for Disease Control and Prevention
        CDC alerts providers to hepatitis cases of unknown origin.
        2022 ([cited 2022 July 29])
        • UK Health Security Agency
        Investigation into acute hepatitis of unknown aaetiology in children in England: technical briefing 3, n.d. vol. 35. 2022 ([cited 2022 July 29])
        • The Lancet Infectious Diseases
        Explaining the unexplained hepatitis in children.
        Lancet Infect Dis. 2022 Jun; 22: 743