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Genomic investigations of unexplained acute hepatitis in children
Version 2 2024-06-19, 22:22
Version 1 2023-11-13, 22:04
journal contribution
posted on 2024-06-19, 22:22 authored by Sofia Morfopoulou, Sarah Buddle, Oscar Enrique Torres Montaguth, Laura Atkinson, Jose Afonso Guerra-Assunco, 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 CD 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, Judith Breuer, Evangelos Bellos, Claire Broderick, Samuel Channon-Wells, Tisham De, Giselle D'Souza, Leire Estramiana Elorrieta, Diego Estrada-Rivadeneyra, Rachel Galassini, Dominic Habgood-Coote, Shea Hamilton, Heather Jackson, James Kavanagh, Stephanie Menikou, Samuel Nichols, Ruud Nijman, Harsita Patel, Ivana Pennisi, Oliver Powell, Ruth Reid, Ortensia Vito, Elizabeth Whittaker, Clare Wilson, Rebecca Womersley, Amina Abdulla, Sarah Darnell, Sobia Mustafa, Pantelis Georgiou, Jesus-Rodriguez Manzano, Nicolas Moser, Michael Carter, Shane Tibby, Jonathan Cohen, Francesca Davis, Julia Kenny, Paul Wellman, Marie White, Matthew Fish, Aislinn Jennings, Shankar-Hari, Katy Fidler, Dan Agranoff, Vivien Richmond, Matthew Seal, Saul Faust, Dan Owen, Ruth Ensom, Sarah McKay, Diana Mondo, Mariya Shaji, Rachel Schranz, Prita Rughnani, Amutha Anpananthar, Susan Liebeschuetz, Anna Riddell, Nosheen Khalid, Ivone Lancoma Malcolm, Teresa Simagan, Mark Peters, Alasdair Bamford, Nazima Pathan, Esther Daubney, Deborah White, Melissa Heightman, Sarah Eisen, Terry Segal, Lucy Wellings, Simon B Drysdale, Nicole Branch, Lisa Hamzah, Heather Jarman, Maggie Nyirenda, Lisa Capozzi, Emma Gardiner, Robert Moots, Magda Nasher, Anita Hanson, Michelle Linforth, Sean O'Riordan, Donna Ellis, Akash Deep, Ivan Caro, Fiona Shackley, Arianna Bellini, Stuart Gormley, Samira Neshat, Barnaby J Scholefield, Ceri Robbins, Helen Winmill, Stephane C Paulus, Andrew J Pollard, Sarah Hopton, Danielle Miller, Zoe Oliver, Sally Beer, Bryony Ward, Shrijana Shrestha, Meeru Gurung, Puja Amatya, Bhishma Pokhrel, Sanjeev Man Bijukchhe, Tim Lubinda, Sarah Kelly, Peter O'Reilly, Federico Martinon-Torres, Antonio Salas, Fernando Alvez Gonzalez, Xabier Bello, Mirian Ben Garcia, Sandra Carnota, Miriam Cebey-Lopez, Maria Jose Curras-Tuala, Carlos Duran Suarez, Luisa Garcia Vicente, Alberto Gomez-Carballa, Jose Gomez Rial, Pilar Leborans Iglesias, Nazareth Martinon-Torres, Jose Maria Martinon Sanchez, Belen Mosquera Perez, Jacobo Pardo-Seco, Lidia Pineiro Rodriguez, Sara Pischedda, Sara Rey Vazquez, Irene Rivero Calle, Carmen Rodriguez-Tenreiro, Lorenzo Redondo-Collazo, Miguel Sadiki Ora, Sonia Seren Fernandez, Cristina Seren Trasorras, Marisol Vilas Iglesias, Enitan D Carrol, Elizabeth Cocklin, Aakash Khanijau, Rebecca Lenihan, Nadia Lewis-Burke, Karen Newal, Sam Romaine, Maria Tsolia, Irini Eleftheriou, Nikos Spyridis, Maria Tambouratzi, Despoina Maritsi, Antonios Marmarinos, Marietta Xagorari, Lourida Panagiota, Pefanis Aggelos, Akinosoglou Karolina, Gogos Charalambos, Maragos Markos, Voulgarelis Michalis, Stergiou Ioanna, Marieke Emonts, Emma Lim, John Isaacs, Kathryn Bell, Stephen Crulley, Daniel Fabian, Evelyn Thomson, Caroline Miller, Ashley Bell, Fabian JS van der Velden, Geoff Shenton, Ashley Price, Owen Treloar, Daisy Thomas, Pablo Rojo, Cristina Epalza, Serena Villaverde, Sonia Marquez, Manuel Gijon, Fatima Machin, Laura Cabello, Irene Hernandez, Lourdes Gutierrez, Angela Manzanares, Taco Kuijpers, Martijn van de Kuip, Marceline van Furth, Merlijn van den Berg, Giske Biesbroek, Floris Verkuil, Carlijn van der Zee, Dasja Pajkrt, Michael Boele van Hensbroek, Dieneke Schonenberg, Mariken Gruppen, Sietse Nagelkerke, Machiel H Jansen, Ines Goetschalckx, Lorenza Romani, Maia De Luca, Sara Chiurchiu, Martina Di Giuseppe, Clementien L Vermont, Henriette A Moll, Dorine M Borensztajn, Nienke N Hagedoorn, Chantal Tan, Joany Zachariasse, W Dik, Ching-Fen Shen, Dace Zavadska, Sniedze Laivacuma, Aleksandra Rudzate, Diana Stoldere, Arta Barzdina, Elza Barzdina, Monta Madelane, Dagne Gravele, Dace Svile, Romain Basmaci, Noemie Lachaume, Pauline Bories, Raja Ben Tkhayat, Laura Cheriaux, Jurate Davoust, Kim-Thanh Ong, Marie Cotillon, Thibault de Groc, Sebastien Le, Nathalie Vergnault, Helene See, Laure Cohen, Alice de Tugny, Nevena Danekova, Marine Mommert-Tripon, Karen Brengel-Pesce, Marko Pokorn, Mojca Kolnik, Tadej Avcin, Tanja Avramoska, Natalija Bahovec, Petra Bogovic, Lidija Kitanovski, Mirijam Nahtigal, Lea Papst, Tina Plankar Srovin, Franc Strle, Anja Srpcic, Katarina Vincek, Michiel van der Flier, Wim JE Tissing, Roelie M Wosten-van Asperen, Sebastiaan J Vastert, Daniel C Vijlbrief, Louis J Bont, Tom FW Wolfs, Coco R Beudeker, Philipp Agyeman, Luregn Schlapbach, Christoph Aebi, Mariama Usman, Stefanie Schluchter, Verena Wyss, Nina Schobi, Elisa Zimmermann, Kathrin Weber, Eric Giannoni, Martin Stocker, Klara M Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Giancarlo Natalucci, Christa Relly, Thomas Riedel, Christoph Berger, Jennifer Holden, Leo Calvo-Bado, Benjamin Evans, Jake Stevens, Peter Matthews, Kyle Billing, Werner Zenz, Alexander Binder, Benno Kohlmaier, Daniela S Kohlfurst, Nina A Schweintzger, Christoph Zurl, Susanne Hosele, Manuel Leitner, Lena Polz, Alexandra Rusu, Glorija Rajic, Bianca Stoiser, Martina Strempfl, Manfred G Sagmeister, Sebastian Bauchinger, Martin Benesch, Astrid Ceolotto, Ernst Eber, Siegfried Gallistl, Harald Haidl, Almuthe Hauer, Christa Hude, Andreas Kapper, Markus Keldorfer, Sabine Loffler, Tobias Niedrist, Heidemarie Pilch, Andreas Pfleger, Klaus Pfurtscheller, Siegfried Rodl, Andrea Skrabl-Baumgartner, Volker Strenger, Elmar Wallner, Dennie Tempel, Danielle van Keulen, Annelieke M Strijbosch, Maike K Tauchert, Ulrich von Both, Laura Kolberg, Patricia Schmied, Irene Alba-Alejandre, Katharina Danhauser, Nikolaus Haas, Florian Hoffmann, Matthias Griese, Tobias Feuchtinger, Sabrina Juranek, Matthias Kappler, Eberhard Lurz, Esther Maier, Karl Reiter, Carola Schoen, Sebastian Schroepf, Shunmay Yeung, Manuel Dewez, David Bath, Elizabeth Fitchett, Fiona Cresswell, Aubrey Cunnington, Jethro Herberg, Mysini Kaforou, Victoria Wright, Lucas Baumard, Clive Hoggart, Sara Hourmat, Ian Maconochie, Naomi Lin, Ivonne Pena Paz, Ladan Ali, Rikke Jorgensen, Salina Persand, Molly Stevens, Eunjung Kim, Benjamin Pierce, Julia Dudley, Emma Tavliavini, Ching-Chuan Liu, Shih-Min Wang, Cristina Balo Farto, Ruth Barral-Arca, Maria Barreiro Castro, Anda BalodeAbstractSince 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.
