Genomic investigations of unexplained acute hepatitis in children

Sofia Morfopoulou, Sarah Buddle, Oscar Enrique Torres Montaguth, Laura Atkinson, José Afonso Guerra-Assunção, Mahdi Moradi Marjaneh, Riccardo Zennezini Chiozzi, Nathaniel Storey, Luis Campos, J. Ciaran Hutchinson, John R. Counsell, Gabriele Pollara, Sunando Roy, Cristina Venturini, Juan F. Antinao Diaz, Ala’a Siam, Luke J. Tappouni, Zeinab Asgarian, Joanne Ng, Killian S. Hanlon, Alexander Lennon, Andrew McArdle, Agata Czap, Joshua Rosenheim, Catarina Andrade, Glenn Anderson, Jack C. D. Lee, Rachel Williams, Charlotte A. Williams, Helena Tutill, Nadua Bayzid, Luz Marina Martin Bernal, Hannah Macpherson, Kylie-Ann Montgomery, Catherine Moore, Kate Templeton, Claire Neill, Matt Holden, Rory Gunson, Samantha J. Shepherd, Priyen Shah, Samantha Cooray, Marie Voice, Michael Steele, Colin Fink, Thomas E. Whittaker, Giorgia Santilli, Paul Gissen, Benedikt B. Kaufer, Jana Reich, Julien Andreani, Peter Simmonds, Dimah K. Alrabiah, Sergi Castellano, Primrose Chikowore, Miranda Odam, Tommy Rampling, Catherine Houlihan, Katja Hoschler, Tiina Talts, Cristina Celma, Suam Gonzalez, Eileen Gallagher, Ruth Simmons, Conall Watson, Sema Mandal, Maria Zambon, Meera Chand, James Hatcher, Surjo De, Kenneth Baillie, Malcolm Gracie Semple, Joanne Martin, Ines Ushiro-Lumb, Mahdad Noursadeghi, Maesha Deheragoda, Nedim Hadzic, Tassos Grammatikopoulos, Rachel Brown, Chayarani Kelgeri, Konstantinos Thalassinos, Simon N. Waddington, Thomas S. Jacques, Emma Thomson, Michael Levin, Julianne R. Brown and Judith Breuer ()
Additional contact information
Sofia Morfopoulou: University College London
Sarah Buddle: University College London
Oscar Enrique Torres Montaguth: University College London
Laura Atkinson: Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust
José Afonso Guerra-Assunção: University College London
Mahdi Moradi Marjaneh: Imperial College London
Riccardo Zennezini Chiozzi: University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London
Nathaniel Storey: Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust
Luis Campos: Great Ormond Street Hospital for Children NHS Foundation Trust
J. Ciaran Hutchinson: Great Ormond Street Hospital for Children NHS Foundation Trust
John R. Counsell: University College London
Gabriele Pollara: University College London
Sunando Roy: University College London
Cristina Venturini: University College London
Juan F. Antinao Diaz: University College London
Ala’a Siam: University College London
Luke J. Tappouni: University College London
Zeinab Asgarian: University College London
Joanne Ng: University College London
Killian S. Hanlon: University College London
Alexander Lennon: Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust
Andrew McArdle: Imperial College London
Agata Czap: University College London
Joshua Rosenheim: University College London
Catarina Andrade: Great Ormond Street Hospital for Children NHS Foundation Trust
Glenn Anderson: Great Ormond Street Hospital for Children NHS Foundation Trust
Jack C. D. Lee: Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust
Rachel Williams: University College London
Charlotte A. Williams: University College London
Helena Tutill: University College London
Nadua Bayzid: University College London
Luz Marina Martin Bernal: University College London
Hannah Macpherson: University College London
Kylie-Ann Montgomery: University College London
Catherine Moore: University Hospital of Wales
Kate Templeton: Edinburgh Royal Infirmary
Claire Neill: Public Health Agency Northern Ireland
Matt Holden: University of St. Andrews
Rory Gunson: West of Scotland Specialist Virology Centre
Samantha J. Shepherd: West of Scotland Specialist Virology Centre
Priyen Shah: Imperial College London
Samantha Cooray: Imperial College London
Marie Voice: University of Warwick Science Park
Michael Steele: University of Warwick Science Park
Colin Fink: University of Warwick Science Park
Thomas E. Whittaker: University College London
Giorgia Santilli: University College London
Paul Gissen: University College London
Benedikt B. Kaufer: Institute of Virology, Freie Universität Berlin
Jana Reich: Institute of Virology, Freie Universität Berlin
Julien Andreani: University of Oxford
Peter Simmonds: University of Oxford
Dimah K. Alrabiah: University College London
Sergi Castellano: University College London
Primrose Chikowore: University of Edinburgh
Miranda Odam: University of Edinburgh
Tommy Rampling: University College London
Catherine Houlihan: University College London
Katja Hoschler: UK Health Security Agency
Tiina Talts: UK Health Security Agency
Cristina Celma: UK Health Security Agency
Suam Gonzalez: UK Health Security Agency
Eileen Gallagher: UK Health Security Agency
Ruth Simmons: UK Health Security Agency
Conall Watson: UK Health Security Agency
Sema Mandal: UK Health Security Agency
Maria Zambon: UK Health Security Agency
Meera Chand: UK Health Security Agency
James Hatcher: Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust
Surjo De: Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust
Kenneth Baillie: University of Edinburgh
Malcolm Gracie Semple: University of Liverpool
Joanne Martin: Centre for Genomics and Child Health, The Blizard Institute, Queen Mary University of London
Ines Ushiro-Lumb: NHS Blood and Transplant
Mahdad Noursadeghi: University College London
Maesha Deheragoda: King’s College Hospital
Nedim Hadzic: King’s College Hospital
Tassos Grammatikopoulos: King’s College Hospital
Rachel Brown: Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust
Chayarani Kelgeri: Liver Unit, Birmingham Women’s and Children’s NHS Foundation Trust
Konstantinos Thalassinos: University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London
Simon N. Waddington: University College London
Thomas S. Jacques: Great Ormond Street Hospital for Children NHS Foundation Trust
Emma Thomson: Medical Research Council–University of Glasgow Centre for Virus Research
Michael Levin: Imperial College London
Julianne R. Brown: Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust
Judith Breuer: University College London

Nature, 2023, vol. 617, issue 7961, 564-573

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06003-w

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