Current knowledge about the outbreak of acute severe hepatitis of unknown origin among children

Background: A recent outbreak of acute severe hepatitis of unknown aetiology (ASHep-UA) among children 16 years old and younger has aroused global concern. Initially reported in central Scotland, the disease has been notified in 35 countries and linked to 22 deaths as of 25 September 2022.
Aim: This review aimed to provide current knowledge about the outbreak of ASHep-UA.
Methods and Results: The websites of the World Health Organization, the UK Health Security Agency, the European Centre for Disease Prevention and Control, the Centers for Disease Control and Prevention, and the PubMed database were searched, based on the search term “acute severe hepatitis of unknown aetiology”. The corresponding reports or literature previously released by the mentioned websites and database were integrated to obtain current information about ASHep-UA.
Conclusion: Even though the potential relevance between ASHep-UA and adenovirus, adeno-associated virus 2, and human herpes viruses was revealed, the aetiology of ASHep-UA is still unknown. More effort should be made to explore whether ASHep-UA is caused by a novel virus or other environmental factors, to generate appropriate treatment strategies
Relevance to patients: ASHep-UA has aroused global concern recently, which may lead to adverse outcomes like liver transplants and death. The present review shares current development and information about the outbreak of acute severe hepatitis of unknown origin among children.
[1] World Health Organization. Acute Hepatitis of Unknown Aetiology-The United Kingdom of Great Britain and Northern Ireland. Geneva: World Health Organization; 2022. Available from: https://www.who.int/emergencies/ disease-outbreak-news/item/Acute-Hepatitis-ofUnknown-Aetiology---the-United-Kingdom-ofGreat-Britain-and-Northern-Ireland [Last accessed on 2022 Jul 19].
[2] World Health Organization. Disease Outbreak News; Acute Hepatitis of Unknown Aetiology in ChildrenMulti-Country. Available from: https://www.who.int/ emergencies/disease-outbreak-news/item/2022-Don400 [Last accessed on 2022 Sep 25].
[3] European Centre for Disease Prevention and Control. Joint ECDC-Who Regional Office for Europe Hepatitis of Unknown Origin in Children Surveillance Bulletin, 26 August, 2022. Available from: https://cdn.ecdc.europa. eu/novhep-surveillance [Last accessed on 2022 Sep 25].
[4] Centers for Disease Control. Technical Report: Acute Hepatitis of Unknown Cause. Available from: https://www. cdc.gov/ncird/investigation/Hepatitis-Unknown-Cause/ Technical-Report.html [Last accessed on 2022 Sep 25].
[5] European Centre for Disease Prevention and Control. Hepatitis of Unknown Origin Reporting Protocol 2022 Version 2.1. Stockholm: ECDC; 2022. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/ Hepatitis-of-Unknown-Origin-Reporting-ProtocolV2.1.pdf [Last accessed on 2022 Jul 19].
[6] UK Health Security Agency. Investigation into Acute Hepatitis of Unknown Aetiology in Children in England. London: UKHSA; 2022. Available from: https://assets. publishing.service.gov.uk/government/uploads/system/ uploads/attachment_data/file/1094573/Acute-HepatitisTechnical-Briefing-4.pdf [Last accessed on 2022 Sep 25].
[7] Marsh K, Tayler R, Pollock L, Roy K, Lakha F, Ho A, et al. Investigation into Cases of Hepatitis of Unknown Aetiology among Young Children, Scotland, 1 January 2022 to 12 April 2022. Euro Surveill 2022;27: 2200318.
[8] Deep A, Grammatikopoulos T, Heaton N, Verma A, Dhawan A. Outbreak of Hepatitis in Children: Clinical Course of Children with Acute Liver Failure Admitted to the Intensive Care Unit. Intensive Care Med 2022;48: 958-62.
[9] UK Health Security Agency. Increase in Acute Hepatitis Cases of Unknown Aetiology in Children. London: UKHSA; 2022. Available from: https://www.gov.uk/ Government/Publications/Hepatitis-Increase-in-AcuteCases-of-Unknown-Aetiology-in-Children/Increasein-Acute-Hepatitis-Cases-of-Unknown-Aetiology-inChildren [Last accessed on 2022 Jul 19].
[10] Nishiura H, Jung SM, Hayashi K. High Population Burden of Omicron Variant (B.1.1.529) is Associated with the Emergence of Severe Hepatitis of Unknown Etiology in Children. Int J Infect Dis 2022;122:30-2.
[11] Chiu CY, Miller SA. Clinical Metagenomics. Nat Rev Genet 2019;20:341-55.
[12] Morfopoulou S, Buddle S, Montaguth OE, Atkinson L, Guerra-Assunção JA, Storey N, et al. Genomic Investigations of Acute Hepatitis of Unknown Aetiology in Children. medRxiv 2022;2022.2007.2028.22277963.
[13] Ho A, Orton R, Tayler R, Asamaphan P, Tong L, Smollett K, et al. Adeno-Associated Virus 2 Infection in Children with Non-A-E Hepatitis. medRxiv 2022;2022.2007.2019.22277425.
[14] UK Health Security Agency. Investigation into Acute Hepatitis of Unknown Aetiology in Children in England. London: UKHSA; 2022. Available from: https://assets. publishing.service.gov.uk/government/uploads/system/ uploads/attachment_data/file/1077027/Acute-HepatitisTechnical-Briefing_3.pdf [Last accessed on 2022 Jul 19].
[15] Guidance for Diagnostic Testing of Cases with Severe Acute Hepatitis of Unknown Aetiology in Children. Stockholm: ECDC; 2022. Available from: https://www.ecdc.europa. eu/Sites/Default/Files/Documents/Guidance_Testing_ Hepatitis_Final.pdf [Last accessed on 2022 Jul 19].
[16] Baker JM, Buchfellner M, Britt W, Sanchez V, Potter JL, Ingram LA, et al. Acute Hepatitis and Adenovirus Infection among Children-Alabama, October 2021-February 2022. Am J Transplant 2022;22:1919-21.
[17] Bányai K, Martella V, Meleg E, Kisfali P, Péterfi Z, Benkö M, et al. Searching for HADV-52, the Putative Gastroenteritis-Associated Human Adenovirus Serotype in Southern Hungary. New Microbiol 2009;32:185-8.
[18] Yang C, Zhu C, Qian Y, Deng J, Zhang B, Zhu R, et al. Application of Human Adenovirus Genotyping by Phylogenetic Analysis in an Outbreak to Identify Nosocomial Infection. Virol Sin 2021;36:393-401.
[19] Lynch JP 3rd, Kajon AE. Adenovirus: Epidemiology, Global Spread of Novel Serotypes, and Advances in Treatment and Prevention. Semin Respir Crit Care Med 2016;37: 586-602.
[20] Zheng N, Wang Y, Rong H, Wang K, Huang X. Human Adenovirus Associated Hepatic Injury. Front Public Health 2022;10:878161.
[21] Yonker LM, Gilboa T, Ogata AF, Senussi Y, Lazarovits R, Boribong BP, et al. Multisystem Inflammatory Syndrome in Children is Driven by Zonulin-Dependent Loss of Gut Mucosal Barrier. J Clin Invest 2021;131:e149633.
[22] Brodin P, Arditi M. Severe Acute Hepatitis in Children: Investigate Sars-Cov-2 Superantigens. Lancet Gastroenterol Hepatol 2022;7:594-5.
[23] Avci E, Abasiyanik F. Autoimmune Hepatitis after SarsCov-2 Vaccine: New-onset or Flare-up? J Autoimmun 2021;125:102745.
[24] Meier AF, Fraefel C, Seyffert M. The Interplay between Adeno-Associated Virus and Its Helper Viruses. Viruses 2020;12:662.
[25] Chen YH, Lou JG, Yang ZH, Chen QJ, Hua CZ, Ye S, et al. Diagnosis, Treatment, and Prevention of Severe Acute Hepatitis of Unknown Etiology in Children. World J Pediatr 2022;18:538-44.