Adeno-associated virus 2 infection in children with non-A–E hepatitis

Authors: Antonia Ho, Richard Orton, Rachel Tayler, Patawee Asamaphan, Vanessa Herder, Christopher Davis, L. Tong, Katherine Smollett, Maria Manali, Jay Allan, Konrad Rawlik, Sarah E. McDonald, Elen Vink, Louisa Pollock, Louise Gannon, Clair Evans, Jim McMenamin, Kirsty Roy, Kimberly Marsh, Titus Divala, Matthew T. G. Holden, Michael Lockhart, David Yirrell, Sandra Currie, Maureen O’Leary, David Henderson, Samantha J. Shepherd, Celia Jackson, Rory Gunson, Alasdair Maclean, Neil McInnes, Amanda Bradley-Stewart, Richard Battle, Jill A. Hollenbach, Paul Henderson, Miranda Odam, Primrose Chikowore, Wilna Oosthuyzen, Meera Chand, Melissa Shea Hamilton, Diego Estrada‐Rivadeneyra, Michael Levin, Nikos Avramidis, Erola Pairo‐Castineira, Véronique Vitart, Craig Wilkie, Aubrey J. Cunnington, Jethro Herberg, Myrsini Kaforou, Victoria Wright, Evangelos Bellos, Claire Broderick, Samuel Channon‐Wells, Samantha Cooray, Tisham De, Giselle D’Souza, Leire Estramiana Elorrieta, Rachel Galassini, Dominic Habgood-Coote, Shea Hamilton, Heather Jackson, James Kavanagh, Mahdi Moradi Marjaneh, Stephanie Menikou, Samuel Nichols, Ruud Nijman, Harsita Patel, Ivana Pennisi, Oliver Powell, Ruth Reid, Priyen Shah, Ortensia Vito, Elizabeth Whittaker, Clare Wilson, Rebecca Womersley, Amina Abdulla, Sarah Darnell, Sobia Mustafa, Pantelis Georgiou, Jesus-Rodriguez Manzano, Nicolas Moser, Ivana Pennisi, Michael J. Carter, Shane M. Tibby, Jonathan Cohen, Francesca Davis, Julia Kenny, Paul Wellman, Marie White, Matthew Fish, A.R. Jennings, Manu Shankar‐Hari, Katy Fidler, Dan Agranoff, Vivien Richmond, Mathew Seal, Saul N. 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, Lauran O’Neill, Nazima Pathan, Esther Daubney, Deborah L. 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 J. Moots, Magda Nasher, Anita Hanson, Michelle Linforth, Séan O’Riordan, Donna Ellis, Akash Deep, Iván Caro, Fiona Shackley, Arianna Bellini, Stuart Gormley, Samira Neshat, Barnaby J. Scholefield, Ceri Robbins, Helen Winmill, Stéphane Paulus, Andrew J. Pollard, Mark Anthony, Sarah Hopton, Danielle Miller, Zoe Oliver, Sally Beer, Bryony Ward, Shrijana Shrestha, Andrew J. Pollard, Meeru Gurung, Puja Amatya, Bhishma Pokhrel, Sanjeev Man Bijukchhe, Tim Lubinda, Sarah Kelly, Peter O’Reilly, Federico Martinón‐Torres, Antonio Salas, Fernando Álvez González, Xabier Bello, Mirian Ben García, Sandra Carnota, Miriam Cebey‐López, María José Currás-Tuala, Carlos Durán Suárez, Luisa García Vicente, Alberto Gómez‐Carballa, José Gómez Rial, Pilar Leboráns Iglesias, Nazareth Martinón-Torres, José María Martinón Sánchez, Belén Mosquera Pérez, Jacobo Pardo‐Seco, Lidia Piñeiro Rodríguez, Sara Pischedda, Sara Rey Vázquez, Irene Rivero‐Calle, Carmen Rodrı́guez-Tenreiro, Lorenzo Redondo-Collazo, Miguel Sadiki Ora, Sonia Serén Fernández, Cristina Serén Trasorras, Marisol Vilas Iglesias, Enitan D. Carrol, Elizabeth Cocklin, Aakash Khanijau, Rebecca Lenihan, Nadia Lewis-Burke, Karen Newall, Sam Romaine, Μαρία Τσολιά, Irini Eleftheriou, Νikos 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 T. Isaacs, Kathryn Bell, Stephen Crulley, Daniel Fabián, Evelyn Thomson, Diane Wallia, Caroline Miller, Ashley Bell, Fabian van der Velden, Geoff Shenton, David Price, Owen Treloar, Daisy Thomas, Pablo Rojo, Cristina Epalza, Serena Villaverde, Sonia Márquez, Manuel Gijón, Fátima Machín, Laura Cabello, Irene Hernández, Lourdes Gutiérrez, Ángela Manzanares, Taco W. Kuijpers, M. Martijn van de Kuip, A. M. Marceline van Furth, J. M. Merlijn van den Berg, Giske Biesbroek, Floris Verkuil, Carlijn C. W. van der Zee, Dasja Pajkrt, Michaël Boele van Hensbroek, D. Schonenberg, Mariken Gruppen, Sietse Q. Nagelkerke, Machiel H. Jansen, Ines Goetschalckx, Lorenza Romani, Maia De Luca, Sara Chiurchiù, Martina Di Giuseppe, Clementien L. Vermont, Henriëtte A. Moll, Dorine Borensztajn, Nienke N. Hagedoorn, Chantal Tan, Joany M. Zachariasse, W. Dik, Ching-Fen Kitty Shen, Dace Zavadska, Sniedze Laivacuma, Aleksandra Rudzate, Diana Stoldere, Arta Bārzdiņa, Elza Barzdina, Monta Madelāne, Dagne Grãvele, Dace Svile, Romain Basmaci, Noémie Lachaume, Pauline Bories, Raja Ben Tkhayat, Laura Chériaux, Juraté Davoust, Kim-Thanh Ong, Marie Cotillon, Thibault de Groc, Sébastien Lê, Nathalie Vergnault, Hélène See, Laure Cohen, Alice de Tugny, Névéna Danékova, Marine Mommert-Tripon, Karen Brengel‐Pesce, Marko Pokorn, Mojca Kolnik, Tadej Avčin, Tanja Avramoska, Natalija Bahovec, Petra Bogovič, Lidija Kitanovski, Mirijam Nahtigal, Lea Papst, Tina Plankar Srovin, Franc Strle, Anja Srpčič, Katarina Vincek, Michiel van der Flier, Wim J. E. Tissing, Roelie M. Wösten‐van Asperen, Sebastiaan J. Vastert, Daniel C. Vijlbrief, Louis Bont, Tom F.W. Wolfs, Coco R. Beudeker, Philipp Agyeman, Luregn J. Schlapbach, Christoph Aebi, Mariama Usman, Stefanie Schlüchter, Verena Wyss, Nina Schöbi, Elisa Zimmermann, Marion Meier, Kathrin Weber, Philipp Agyeman, Luregn J. Schlapbach, Éric Giannoni, Martin Stocker, Klara M. Posfay‐Barbe, Ulrich Heininger, Sara Bernhard‐Stirnemann, Anita Niederer-Loher, Christian R. Kahlert, Giancarlo Natalucci, Christa Relly, Thomas Riedel, Christoph Aebi, Christoph Berger, Colin G. Fink, Marie Voice, Leo Calvo‐Bado, Michael Steele, Jennifer Holden, B. J. K. Evans, Jake Stevens, Peter Matthews, Kyle Billing, Werner Zenz, Alexander Binder, Benno Kohlmaier, Daniela S. Kohlfürst, Nina A. Schweintzger, Christoph Zurl, Susanne Hösele, Manuel Leitner, Lena Pölz, 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 Löffler, Tobias Niedrist, Heidemarie Pilch, Andreas Pfleger, Klaus Pfurtscheller, Siegfried Rödl, Andrea Skrabl‐Baumgartner, Volker Strenger, Elmar Wallner, Dennie Tempel, Daniëlle 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 M. Maier, Karl Reiter, Carola Schoen, Sebastian Schroepf, Shunmay Yeung, Manuel Dewez, David Bath, Elizabeth Fitchett, Fiona V Cresswell, Saidykhan Momodou, Effua Usuf, Ebrahim Ndure, Kalifa Bojang, Anna Roca, Isatou Sarr, Isatou Sarr, ISARIC4C Investigators, Gail Carson, Peter Openshaw, Jake Dunning, Laura Merson, Clark D Russell, David A. Dorward, Maria Zambon, Meera Chand, Richard S. Tedder, Saye Khoo, Lance Turtle, Tom Solomon, Samreen Ijaz, Tom Fletcher, Emma C. Thomson, Nicholas Price, Judith Breuer, Thushan I. de Silva, Chloe Donohue, Hayley Hardwick, Lauren Obosi, Sara Clohisey, Andrew Law, Lucy Norris, Sarah Tait, Murray Wham, Richard E. Clark, Audrey Coutts, Lorna Donnelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy, Nicola Wrobel, Victoria Shaw, Katie A. Ahmed, J. A. Armstrong, Lauren Lett, Jane A. Armstrong, Louisa Pollock, Shyla Kishore, Helen Brotherton, Lawrence E. Armstrong, Andrew Mitra, Anna Dall, Kristýna Böhmová, Sheena Logan, Louise Gannon, Ken Agwuh, Srikanth Chukkambotla, Ingrid DuRand, Duncan Fullerton, Sanjeev Gar, Clive Graham, Tassos Grammatikopoulos, Stuart Hartshorn, Luke Hodgson, Paul Jennings, George Koshy, Tamás Leiner, James Limb, Jeff Little, Sheena Logan, Jeff Little, Fiona McGill, Craig F. Morris, John A. Morrice, David A. Price, Henrik Reschreiter, Tim Reynolds, Paul Whittaker, Thomas Jordan, Rachel Tayler, Clare Irving, Katherine Jack, Maxine Ramsay, Margaret Millar, Barry Milligan, Naomi Hickey, Maggie Connon, Catriona Ward, Laura Beveridge, Susan MacFarlane, Karen Leitch, Claire Bell, Lauren Finlayson, Joy Dawson, Janie Candlish, Laura McGenily, Tara Roome, Cynthia Diaba, Jasmine Player, Natassia Powell, Ruth Howman, Sara Burling, Sharon Floyd, Sarah Farmer, Susie Ferguson, Susan Hope, Lucy Rubick, Rachel Swingler, Emma Collins, Collette Spencer, Amaryl Jones, Barbara A. Wilson, Diane Armstrong, Mark Birt, Holly Dickinson, Rosemary Harper, Darran Martin, Amy Roff, Sarah Mills, Massimo Palmarini, Surajit Ray, David L. Robertson, Ana da Silva Filipe, Brian J. Willett, Judith Breuer, Brian J. Willett, David M. Turner, J. Kenneth Baillie, Emma C. Thomson, J. Kenneth Baillie, Emma C. Thomson, Emma C. Thomson - Nature 2023 cited by 171

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.