Genomic investigations of unexplained acute hepatitis in children

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, 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, 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, D?rta, 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., 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 ORCID: https://orcid.org/0000-0002-4475-1733, Kelgeri, Chayarani, Thalassinos, Konstantinos, Waddington, Simon N., Jacques, Thomas S., Thomson, Emma, Levin, Michael, Brown, Julianne R. and Breuer, Judith 2023. Genomic investigations of unexplained acute hepatitis in children. Nature 617 (7961) , pp. 564-573. 10.1038/s41586-023-06003-w

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (10MB) | Preview

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Nature Research
ISSN:	0028-0836
Date of First Compliant Deposit:	26 July 2023
Date of Acceptance:	23 March 2023
Last Modified:	12 Sep 2023 06:09
URI:	https://orca.cardiff.ac.uk/id/eprint/161284

Actions (repository staff only)

Edit Item