Genomic investigations of unexplained acute hepatitis in children

Sofia Morfopoulou, Sarah Buddle, Oscar Enrique Torres Montaguth, DIAMONDS Consortium, PERFORM consortium, Dace Zavadska (Member of the Working Group), Sniedze Laivacuma (Member of the Working Group), Aleksandra Rudzāte (Member of the Working Group), Arta Barzdina (Member of the Working Group), Monta Madelane (Member of the Working Group), Dagne Grāvele, Anda Balode (Member of the Working Group), Ilze Grope (Member of the Working Group), Anija Meiere (Member of the Working Group), Ieva Nokalna (Member of the Working Group), Jana Pavare (Member of the Working Group), Zanda Pucuka (Member of the Working Group), Urzula Nora Urbane (Member of the Working Group), Katrina Selecka (Member of the Working Group), Aleksandra Sidorova (Member of the Working Group)

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Original languageEnglish
Pages (from-to)564-573
Number of pages10
Issue number7961
Publication statusPublished - 30 Mar 2023

Field of Science*

  • 3.2 Clinical medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database


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