Genomic investigations of unexplained acute hepatitis in children Journal Articles uri icon

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abstract

  • AbstractSince 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.

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 CD
  • 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
  • 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 JS
  • 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 JE
  • Wösten-van Asperen, Roelie M
  • Vastert, Sebastiaan J
  • Vijlbrief, Daniel C
  • Bont, Louis J
  • Wolfs, Tom FW
  • 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
  • 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 MA
  • 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, GPJM
  • van Leur, M
  • Heidema, J
  • de Haan, L
  • Miedema, CJ
  • Neeleman, C
  • Obihara, CC
  • Tramper-Stranders, GA
  • 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, JM
  • Schonenberg, D
  • Barendregt, AM
  • Pajkrt, D
  • van der Kuip, M
  • van Furth, AM
  • Sprenkeler, Evelien
  • Zandstra, Judith
  • van Mierlo, G
  • Geissler, J
  • Carson, Gail
  • Openshaw, Peter JM
  • Dunning, Jake
  • Merson, Laura
  • Russell, Clark D
  • Dorward, David
  • Tedder, Richard S
  • Khoo, Say
  • Turtle, Lance CW
  • Solomon, Tom
  • Ijaz, Samreen
  • Fletcher, Tom
  • Palmarini, Massimo
  • Ho, Antonia YW
  • 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

publication date

  • May 18, 2023

published in