Genomic investigations of unexplained acute hepatitis in children
Authors: Morfopoulou Sofia , Buddle Sarah , Torres Montaguth Oscar Enrique , Atkinson Laura , Guerra-Assunção José Afonso , Moradi Marjaneh Mahdi , Zennezini Chiozzi Riccardo , Storey Nathaniel , Campos Luis , Hutchinson J. Ciaran , Counsell John R. , Pollara Gabriele , Roy Sunando , Venturini Cristina , Antinao Diaz Juan F. , Siam Ala’a , Tappouni Luke J. , Asgarian Zeinab , Ng Joanne , Hanlon Killian S. , Lennon Alexander , McArdle Andrew , Czap Agata , Rosenheim Joshua , Andrade Catarina , Anderson Glenn , Lee Jack C. D. , Williams Rachel , Williams Charlotte A. , Tutill Helena , Bayzid Nadua , Martin Bernal Luz Marina , Macpherson Hannah , Montgomery Kylie-Ann , Moore Catherine , Templeton Kate , Neill Claire , Holden Matt , Gunson Rory , Shepherd Samantha J. , Shah Priyen , Cooray Samantha , Voice Marie , Steele Michael , Fink Colin , Whittaker Thomas E. , Santilli Giorgia , Gissen Paul , Kaufer Benedikt B. , Reich Jana , Andreani Julien , Simmonds Peter , Alrabiah Dimah K. , Castellano Sergi , Chikowore Primrose , Odam Miranda , Rampling Tommy , Houlihan Catherine , Hoschler Katja , Talts Tiina , Celma Cristina , Gonzalez Suam , Gallagher Eileen , Simmons Ruth , Watson Conall , Mandal Sema , Zambon Maria , Chand Meera , Hatcher James , De Surjo , Baillie Kenneth , Semple Malcolm Gracie ,   DIAMONDS Consortium, Bellos Evangelos , Broderick Claire , Channon-Wells Samuel , De Tisham , D’Souza Giselle , Elorrieta Leire Estramiana , Estrada-Rivadeneyra Diego , Galassini Rachel , Habgood-Coote Dominic , Hamilton Shea , Jackson Heather , Kavanagh James , Marjaneh Mahdi Moradi , Menikou Stephanie , Nichols Samuel , Nijman Ruud , Patel Harsita , Pennisi Ivana , Powell Oliver , Reid Ruth , Vito Ortensia , Whittaker Elizabeth , Wilson Clare , Womersley Rebecca , Abdulla Amina , Darnell Sarah , Mustafa Sobia , Georgiou Pantelis , Manzano Jesus-Rodriguez , Moser Nicolas , Carter Michael , Tibby Shane , Cohen Jonathan , Davis Francesca , Kenny Julia , Wellman Paul , White Marie , Fish Matthew , Jennings Aislinn , Shankar-Hari  , Fidler Katy , Agranoff Dan , Richmond Vivien , Seal Matthew , Faust Saul , Owen Dan , Ensom Ruth , McKay Sarah , Mondo Diana , Shaji Mariya , Schranz Rachel , Rughnani Prita , Anpananthar Amutha , Liebeschuetz Susan , Riddell Anna , Khalid Nosheen , Malcolm Ivone Lancoma , Simagan Teresa , Peters Mark , Bamford Alasdair , Pathan Nazima , Daubney Esther , White Deborah , Heightman Melissa , Eisen Sarah , Segal Terry , Wellings Lucy , Drysdale Simon B. , Branch Nicole , Hamzah Lisa , Jarman Heather , Nyirenda Maggie , Capozzi Lisa , Gardiner Emma , Moots Robert , Nasher Magda , Hanson Anita , Linforth Michelle , O’Riordan Sean , Ellis Donna , Deep Akash , Caro Ivan , Shackley Fiona , Bellini Arianna , Gormley Stuart , Neshat Samira , Scholefield Barnaby J. , Robbins Ceri , Winmill Helen , Paulus Stéphane C. , Pollard Andrew J. , Hopton Sarah , Miller Danielle , Oliver Zoe , Beer Sally , Ward Bryony , Shrestha Shrijana , Gurung Meeru , Amatya Puja , Pokhrel Bhishma , Bijukchhe Sanjeev Man , Lubinda Tim , Kelly Sarah , O’Reilly Peter , Martinón-Torres Federico , Salas Antonio , González Fernando Álvez , Bello Xabier , García Mirian Ben , Carnota Sandra , Cebey-López Miriam , Curras-Tuala María José , Suárez Carlos Durán , Vicente Luisa García , Gómez-Carballa Alberto , Rial Jose Gómez , Iglesias Pilar Leboráns , Martinón-Torres Nazareth , Sánchez José María Martinón , Pérez Belén Mosquera , Pardo-Seco Jacobo , Rodríguez Lidia Piñeiro , Pischedda Sara , Vázquez Sara Rey , Calle Irene Rivero , Rodríguez-Tenreiro Carmen , Redondo-Collazo Lorenzo , Ora Miguel Sadiki , Fernández Sonia Serén , Trasorras Cristina Serén , Iglesias Marisol Vilas , Carrol Enitan D. , Cocklin Elizabeth , Khanijau Aakash , Lenihan Rebecca , Lewis-Burke Nadia , Newal Karen , Romaine Sam , Tsolia Maria , Eleftheriou Irini , Spyridis Nikos , Tambouratzi Maria , Maritsi Despoina , Marmarinos Antonios , Xagorari Marietta , Panagiota Lourida , Aggelos Pefanis , Karolina Akinosoglou , Charalambos Gogos , Markos Maragos , Michalis Voulgarelis , Ioanna Stergiou , Emonts Marieke , Lim Emma , Isaacs John , Bell Kathryn , Crulley Stephen , Fabian Daniel , Thomson Evelyn , Miller Caroline , Bell Ashley , van der Velden Fabian J. S. , Shenton Geoff , Price Ashley , Treloar Owen , Thomas Daisy , Rojo Pablo , Epalza Cristina , Villaverde Serena , Márquez Sonia , Gijón Manuel , Machín Fátima , Cabello Laura , Hernández Irene , Gutiérrez Lourdes , Manzanares Ángela , Kuijpers Taco , van de Kuip Martijn , van Furth Marceline , van den Berg Merlijn , Biesbroek Giske , Verkuil Floris , van der Zee Carlijn , Pajkrt Dasja , van Hensbroek Michael Boele , Schonenberg Dieneke , Gruppen Mariken , Nagelkerke Sietse , Jansen Machiel H. , Goetschalckx Ines , Romani Lorenza , Luca Maia De , Chiurchiù Sara , Giuseppe Martina Di , Vermont Clementien L. , Moll Henriëtte A. , Borensztajn Dorine M. , Hagedoorn Nienke N. , Tan Chantal , Zachariasse Joany , Dik W. , Shen Ching-Fen , Zavadska Dace , Laivacuma Sniedze , Rudzate Aleksandra , Stoldere Diana , Barzdina Arta , Barzdina Elza , Laivacuma Sniedze , Madelane Monta , Gravele Dagne , Svile Dace , Basmaci Romain , Lachaume Noémie , Bories Pauline , Tkhayat Raja Ben , Chériaux Laura , Davoust Juraté , Ong Kim-Thanh , Cotillon Marie , de Groc Thibault , Le Sébastien , Vergnault Nathalie , Sée Hélène , Cohen Laure , de Tugny Alice , Danekova Nevena , Mommert-Tripon Marine , Brengel-Pesce Karen , Pokorn Marko , Kolnik Mojca , Avcin Tadej , Avramoska Tanja , Bahovec Natalija , Bogovic Petra , Kitanovski Lidija , Nahtigal Mirijam , Papst Lea , Srovin Tina Plankar , Strle Franc , Srpcic Anja , Vincek Katarina , van der Flier Michiel , Tissing Wim J. E. , Wösten-van Asperen Roelie M. , Vastert Sebastiaan J. , Vijlbrief Daniel C. , Bont Louis J. , Wolfs Tom F. W. , Beudeker Coco R. , Agyeman Philipp , Schlapbach Luregn , Aebi Christoph , Usman Mariama , Schlüchter Stefanie , Wyss Verena , Schöbi Nina , Zimmermann Elisa , Weber Kathrin , Giannoni Eric , Stocker Martin , Posfay-Barbe Klara M. , Heininger Ulrich , Bernhard-Stirnemann Sara , Niederer-Loher Anita , Kahlert Christian , Natalucci Giancarlo , Relly Christa , Riedel Thomas , Berger Christoph , Holden Jennifer , Calvo-Bado Leo , Evans Benjamin , Stevens Jake , Matthews Peter , Billing Kyle , Zenz Werner , Binder Alexander , Kohlmaier Benno , Kohlfürst Daniela S. , Schweintzger Nina A. , Zurl Christoph , Hösele Susanne , Leitner Manuel , Pölz Lena , Rusu Alexandra , Rajic Glorija , Stoiser Bianca , Strempfl Martina , Sagmeister Manfred G. , Bauchinger Sebastian , Benesch Martin , Ceolotto Astrid , Eber Ernst , Gallistl Siegfried , Haidl Harald , Hauer Almuthe , Hude Christa , Kapper Andreas , Keldorfer Markus , Löffler Sabine , Niedrist Tobias , Pilch Heidemarie , Pfleger Andreas , Pfurtscheller Klaus , Rödl Siegfried , Skrabl-Baumgartner Andrea , Strenger Volker , Wallner Elmar , Tempel Dennie , van Keulen Danielle , Strijbosch Annelieke M. , Tauchert Maike K. , von Both Ulrich , Kolberg Laura , Schmied Patricia , Alba-Alejandre Irene , Danhauser Katharina , Haas Nikolaus , Hoffmann Florian , Griese Matthias , Feuchtinger Tobias , Juranek Sabrina , Kappler Matthias , Lurz Eberhard , Maier Esther , Reiter Karl , Schoen Carola , Schroepf Sebastian , Yeung Shunmay , Dewez Manuel , Bath David , Fitchett Elizabeth , Cresswell Fiona ,   PERFORM Consortium, Cunnington Aubrey , Herberg Jethro , Kaforou Mysini , Wright Victoria , Baumard Lucas , Hoggart Clive , Hourmat Sara , Maconochie Ian , Lin Naomi , Paz Ivonne Pena , Ali Ladan , Jorgensen Rikke , Persand Salina , Stevens Molly , Kim Eunjung , Pierce Benjamin , Dudley Julia , Tavliavini Emma , Liu Ching-Chuan , Wang Shih-Min , Farto Cristina Balo , Barral-Arca Ruth , Castro Maria Barreiro , Balode Anda , Deksne Dārta , Grope Ilze , Meiere Anija , Nokalna Ieva , Pavare Jana , Pucuka Zanda , Selecka Katrina , Sidorova Aleksandra , Urbane Urzula Nora , Usuf Effua , Bojang Kalifa , Zaman Syed M. A. , Secka Fatou , Anderson Suzanne , Sarr Anna RocaIsatou , Saidykhan Momodou , Darboe Saffiatou , Ceesay Samba , D’alessandro Umberto , Schlapbach Luregn J. , Paulus Stéphane , Jennings Rebecca , Johnston Joanne , Leigh Simon , Newall Karen , Marmarinos Antonis , Syggelou Kelly , Baumgart Hinrich , Benesch Martin , Gores Gunther , Krenn Larissa , Nordberg Gudrun , Sperl Matthias , Stampfer Laura , Till Holger , Trobisch Andreas , Dewez Juan Emmanuel , Hibberd Martin , Miners Alec , Nijman Ruud , Wedderburn Catherine , Meierford Anne , Leurent Baptiste , de Groot Ronald , van der Flier Michiel , de Jonge Marien I. , van Aerde Koen , Alkema Wynand , van den Broek Bryan , Gloerich Jolein , van Gool Alain J. , Henriet Stefanie , Huijnen Martijn , Philipsen Ria , Willems Esther , Gerrits G. P. J. M. , van Leur M. , Heidema J. , de Haan L. , Miedema C. J. , Neeleman C. , Obihara C. C. , Tramper-Stranders G. A. , Kandasamy Rama , Paulus Stéphane , Carter Michael J. , O’Connor Daniel , Bibi Sagida , Kelly Dominic F. , Thorson Stephen , Ansari Imran , Murdoch David R. , Valentine Lucille , Allen Karen , Chan Adora , Devine Kirsty , King Sharon , McAlinden Paul , McDonald Sam , McDonnell Anne , Pickering Ailsa , Wood Amanda , Wallia Diane , Woodsford Phil , Baxter Frances , Rhodes Mathew , Agbeko Rachel , Mackerness Christine , Baas Bryan , Kloosterhuis Lieke , Oosthoek Wilma , Arif Tasnim , Bennet Joshua , Collings Kalvin , van der Giessen Ilona , Martin Alex , Rashid Aqeela , Rowlands Emily , de Vries Gabriella , van der Velden Fabian , Martin Mike , Mistry Ravi , Zwerenz Manuela , Buschbeck Judith , Bidlingmaier Christoph , Binder Vera , Keil Julia , Muench Georg , Mallet François , Pachot Alexandre , Mommert Marine , Pokorn Marko , Prunk Petra , Osterman Veronika , Kuijpers Taco , Jongerius Ilse , van den Berg J. M. , Schonenberg D. , Barendregt A. M. , Pajkrt D. , van der Kuip M. , van Furth A. M. , Sprenkeler Evelien , Zandstra Judith , van Mierlo G. , Geissler J. ,   ISARIC 4C Investigators, Carson Gail , Openshaw Peter J. M. , Dunning Jake , Merson Laura , Russell Clark D. , Dorward David , Tedder Richard S. , Khoo Say , Turtle Lance C. W. , Solomon Tom , Ijaz Samreen , Fletcher Tom , Palmarini Massimo , Ho Antonia Y. W. , Price Nicholas , de Silva Thushan , Donohue Chloe , Hardwick Hayley , Oosthuyzen Wilna , Obosi Lauren , Clohisey Sara , Law Andrew , Norris Lucy , Tait Sarah , Wham Murray , Clark Richard , Coutts Audrey , Donelly Lorna , Fawkes Angie , Gilchrist Tammy , Hafezi Katarzyna , MacGillivray Louise , Maclean Alan , McCafferty Sarah , Morrice Kirstie , Murphy Lee , Wrobel Nicola , McDonald Sarah E. , Shaw Victoria , Armstrong Jane A. , Lett Lauren , Henderson Paul , Pollock Louisa , Kishore Shyla , Brotherton Helen , Armstrong Lawrence , Mita Andrew , Dall Anna , Bohmova Kristyna , Logan Sheena , Gannon Louise , Agwuh Ken , Chukkambotla Srikanth , DuRand Ingrid , Fullerton Duncan , Garg Sanjeev , Graham Clive , Hartshorn Stuart , Hodgson Luke , Jennings Paul , Koshy George , Leiner Tamas , Limb James , Little Jeff , Matovu Elijah , McGill Fiona , Morris Craig , Morrice John , Price David , Reschreiter Henrik , Reynolds Tim , Whittaker Paul , Tayler Rachel , Irving Clare , Ramsay Maxine , Millar Margaret , Milligan Barry , Hickey Naomy , Connon Maggie , Ward Catriona , Beveridge Laura , MacFarlane Susan , Leitch Karen , Bell Claire , Finlayson Lauren , Dawson Joy , Candlish Janie , McGenily Laura , Roome Tara , Diaba Cynthia , Player Jasmine , Powell Natassia , Howman Ruth , Burling Sara , Floyd Sharon , Farmer Sarah , Ferguson Susie , Hope Susan , Rubick Lucy , Swingler Rachel , Collins Emma , Spencer Collette , Jones Amaryl , Wilson Barbara , Armstrong Diane , Birt Mark , Dickinson Holly , Harper Rosemary , Martin Darran , Roff Amy , Mills Sarah , Martin Joanne , Ushiro-Lumb Ines , Noursadeghi Mahdad , Deheragoda Maesha , Hadzic Nedim , Grammatikopoulos Tassos , Brown Rachel , Kelgeri Chayarani , Thalassinos Konstantinos , Waddington Simon N. , Jacques Thomas S. , Thomson Emma , Levin Michael , Brown Julianne R. , Breuer Judith 
Published: April 2023

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.