Genomic investigations of unexplained acute hepatitis in children

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 particip...

Descripción completa

Detalles Bibliográficos
Autores: Morfopoulou, S., Buddle, S., Torres Montaguth, O.E., Atkinson, L., Guerra-Assunção, J.A., Moradi Marjaneh, M., Zennezini Chiozzi, R., Storey, N., Campos, L., Hutchinson, J.C., Counsell, J.R., Pollara, G., Roy, S., Venturini, C., Antinao Diaz, J.F., Siam, A., Tappouni, L.J., Asgarian, Z., Ng, J., Hanlon, K.S., Lennon, A., McArdle, A., Czap, A., Rosenheim, J., Andrade, C., Anderson, G., Lee, J.C.D., Williams, R., Williams, C.A., Tutill, H., Bayzid, N., Martin Bernal, L.M., Macpherson, H., Montgomery, K.-A., Moore, C., Templeton, K., Neill, C., Holden, M., Gunson, R., Shepherd, S.J., Shah, P., Cooray, S., Voice, M., Steele, M., Fink, C., Whittaker, T.E., Santilli, G., Gissen, P., Kaufer, B.B., Reich, J., Andreani, J., Simmonds, P., Alrabiah, D.K., Castellano, S., Chikowore, P., Odam, M., Rampling, T., Houlihan, C., Hoschler, K., Talts, T., Celma, C., Gonzalez, S., Gallagher, E., Simmons, R., Watson, C., Mandal, S., Zambon, M., Chand, M., Hatcher, J., De, S., Baillie, K., Semple, M.G., Bellos, E., Broderick, C., Channon-Wells, S., De, T., D'Souza, G., Elorrieta, L.E., Estrada-Rivadeneyra, D., Galassini, R., Habgood-Coote, D., Hamilton, S., Jackson, H., Kavanagh, J., Marjaneh, M.M., Menikou, S., Nichols, S., Nijman, R., Patel, H., Pennisi, I., Powell, O., Reid, R., Vito, O., Whittaker, E., Wilson, C., Womersley, R., Abdulla, A., Darnell, S., Mustafa, S., Georgiou, P., Manzano, J.-R., Moser, N., Carter, M., Tibby, S., Cohen, J., Davis, F., Kenny, J., Wellman, P., White, M., Fish, M., Jennings, A., Shankar-Hari, null, Fidler, K., Agranoff, D., Richmond, V., Seal, M., Faust, S., Owen, D., Ensom, R., McKay, S., Mondo, D., Shaji, M., Schranz, R., Rughnani, P., Anpananthar, A., Liebeschuetz, S., Riddell, A., Khalid, N., Malcolm, I.L., Simagan, T., Peters, M., Bamford, A., Pathan, N., Daubney, E., White, D., Heightman, M., Eisen, S., Segal, T., Wellings, L., Drysdale, S.B., Branch, N., Hamzah, L., Jarman, H., Nyirenda, M., Capozzi, L., Gardiner, E., Moots, R., Nasher, M., Hanson, A., Linforth, M., O'Riordan, S., Ellis, D., Deep, A., Caro, I., Shackley, F., Bellini, A., Gormley, S., Neshat, S., Scholefield, B.J., Robbins, C., Winmill, H., Paulus, S.C., Pollard, A.J., Hopton, S., Miller, D., Oliver, Z., Beer, S., Ward, B., Shrestha, S., Gurung, M., Amatya, P., Pokhrel, B., Bijukchhe, S.M., Lubinda, T., Kelly, S., O'Reilly, P., Martinón Torres, Federico, Salas Ellacuriaga, Antonio, González, F.Á., Bello, X., García, M.B., Carnota, S., Cebey-López, M., Currás Tuala, María José, Suárez, C.D., Vicente, L.G., Gómez Carballa, Alberto, Rial, J.G., Iglesias, P.L., Martinón-Torres, N., Martinón Sánchez, José María, Pardo Seco, Jacobo José, Rodríguez, L.P., Pischedda, Sara, Vázquez, S.R., Calle, I.R., Rodríguez-Tenreiro, C., Redondo Collazo, Lorenzo, Ora, M.S., Fernández, S.S., Trasorras, C.S., Iglesias, M.V., Carrol, E.D., Cocklin, E., Khanijau, A., Lenihan, R., Lewis-Burke, N., Newal, K., Romaine, S., Tsolia, M., Eleftheriou, I., Spyridis, N., Tambouratzi, M., Maritsi, D., Marmarinos, A., Xagorari, M., Panagiota, L., Aggelos, P., Karolina, A., Charalambos, G., Markos, M., Michalis, V., Ioanna, S., Emonts, M., Lim, E., Isaacs, J., Bell, K., Crulley, S., Fabian, D., Thomson, E., Miller, C., Bell, A., van der Velden, F.J.S., Shenton, G., Price, A., Treloar, O., Thomas, D., Rojo, P., Epalza, C., Villaverde, S., Márquez, S., Gijón, M., Machín, F., Cabello, L., Hernández, I., Gutiérrez, L., Manzanares, Á., Kuijpers, T., van de Kuip, M., van Furth, M., van den Berg, M., Biesbroek, G., Verkuil, F., van der Zee, C., Pajkrt, D., van Hensbroek, M.B., Schonenberg, D., Gruppen, M., Nagelkerke, S., Jansen, M.H., Goetschalckx, I., Romani, L., Luca, M.D., Chiurchiù, S., Giuseppe, M.D., Vermont, C.L., Moll, H.A., Borensztajn, D.M., Hagedoorn, N.N., Tan, C., Zachariasse, J., Dik, W., Shen, C.-F., Zavadska, D., Laivacuma, S., Rudzate, A., Stoldere, D., Barzdina, A., Barzdina, E., Madelane, M., Gravele, D., Svile, D., Basmaci, R., Lachaume, N., Bories, P., Tkhayat, R.B., Chériaux, L., Davoust, J., Ong, K.-T., Cotillon, M., de Groc, T., Le, S., Vergnault, N., Sée, H., Cohen, L., de Tugny, A., Danekova, N., Mommert-Tripon, M., Brengel-Pesce, K., Pokorn, M., Kolnik, M., Avcin, T., Avramoska, T., Bahovec, N., Bogovic, P., Kitanovski, L., Nahtigal, M., Papst, L., Srovin, T.P., Strle, F., Srpcic, A., Vincek, K., van der Flier, M., Tissing, W.J.E., Wösten-van Asperen, R.M., Vastert, S.J., Vijlbrief, D.C., Bont, L.J., Wolfs, T.F.W., Beudeker, C.R., Agyeman, P., Schlapbach, L., Aebi, C., Usman, M., Schlüchter, S., Wyss, V., Schöbi, N., Zimmermann, E., Weber, K., Giannoni, E., Stocker, M., Posfay-Barbe, K.M., Heininger, U., Bernhard-Stirnemann, S., Niederer-Loher, A., Kahlert, C., Natalucci, G., Relly, C., Riedel, T., Berger, C., Holden, J., Calvo-Bado, L., Evans, B., Stevens, J., Matthews, P., Billing, K., Zenz, W., Binder, A., Kohlmaier, B., Kohlfürst, D.S., Schweintzger, N.A., Zurl, C., Hösele, S., Leitner, M., Pölz, L., Rusu, A., Rajic, G., Stoiser, B., Strempfl, M., Sagmeister, M.G., Bauchinger, S., Benesch, M., Ceolotto, A., Eber, E., Gallistl, S., Haidl, H., Hauer, A., Hude, C., Kapper, A., Keldorfer, M., Löffler, S., Niedrist, T., Pilch, H., Pfleger, A., Pfurtscheller, K., Rödl, S., Skrabl-Baumgartner, A., Strenger, V., Wallner, E., Tempel, D., van Keulen, D., Strijbosch, A.M., Tauchert, M.K., von Both, U., Kolberg, L., Schmied, P., Alba-Alejandre, I., Danhauser, K., Haas, N., Hoffmann, F., Griese, M., Feuchtinger, T., Juranek, S., Kappler, M., Lurz, E., Maier, E., Reiter, K., Schoen, C., Schroepf, S., Yeung, S., Dewez, M., Bath, D., Fitchett, E., Cresswell, F., Cunnington, A., Herberg, J., Kaforou, M., Wright, V., Baumard, L., Hoggart, C., Hourmat, S., Maconochie, I., Lin, N., Paz, I.P., Ali, L., Jorgensen, R., Persand, S., Stevens, M., Kim, E., Pierce, B., Dudley, J., Tavliavini, E., Liu, C.-C., Wang, S.-M., Farto, C.B., Barral-Arca, R., Castro, M.B., Balode, A., Deksne, D., Grope, I., Meiere, A., Nokalna, I., Pavare, J., Pucuka, Z., Selecka, K., Sidorova, A., Urbane, U.N., Usuf, E., Bojang, K., Zaman, S.M.A., Secka, F., Anderson, S., Sarr, A.R.I., Saidykhan, M., Darboe, S., Ceesay, S., D'alessandro, U., Schlapbach, L.J., Paulus, S., Jennings, R., Johnston, J., Leigh, S., Newall, K., Syggelou, K., Baumgart, H., Gores, G., Krenn, L., Nordberg, G., Sperl, M., Stampfer, L., Till, H., Trobisch, A., Dewez, J.E., Hibberd, M., Miners, A., Wedderburn, C., Meierford, A., Leurent, B., de Groot, R., de Jonge, M.I., van Aerde, K., Alkema, W., van den Broek, B., Gloerich, J., van Gool, A.J., Henriet, S., Huijnen, M., Philipsen, R., Willems, E., 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, R., Carter, M.J., O'Connor, D., Bibi, S., Kelly, D.F., Thorson, S., Ansari, I., Murdoch, D.R., Valentine, L., Allen, K., Chan, A., Devine, K., King, S., McAlinden, P., McDonald, S., McDonnell, A., Pickering, A., Wood, A., Wallia, D., Woodsford, P., Baxter, F., Rhodes, M., Agbeko, R., Mackerness, C., Baas, B., Kloosterhuis, L., Oosthoek, W., Arif, T., Bennet, J., Collings, K., van der Giessen, I., Martin, A., Rashid, A., Rowlands, E., de Vries, G., van der Velden, F., Martin, M., Mistry, R., Zwerenz, M., Buschbeck, J., Bidlingmaier, C., Binder, V., Keil, J., Muench, G., Mallet, F., Pachot, A., Mommert, M., Prunk, P., Osterman, V., Jongerius, I., van den Berg, J.M., Barendregt, A.M., van der Kuip, M., van Furth, A.M., Sprenkeler, E., Zandstra, J., van Mierlo, G., Geissler, J., Carson, G., Openshaw, P.J.M., Dunning, J., Merson, L., Russell, C.D., Dorward, D., Tedder, R.S., Khoo, S., Turtle, L.C.W., Solomon, T., Ijaz, S., Fletcher, T., Palmarini, M., Ho, A.Y.W., Price, N., de Silva, T., Donohue, C., Hardwick, H., Oosthuyzen, W., Obosi, L., Clohisey, S., Law, A., Norris, L., Tait, S., Wham, M., Clark, R., Coutts, A., Donelly, L., Fawkes, A., Gilchrist, T., Hafezi, K., MacGillivray, L., Maclean, A., McCafferty, S., Morrice, K., Murphy, L., Wrobel, N., McDonald, S.E., Shaw, V., Armstrong, J.A., Lett, L., Henderson, P., Pollock, L., Kishore, S., Brotherton, H., Armstrong, L., Mita, A., Dall, A., Bohmova, K., Logan, S., Gannon, L., Agwuh, K., Chukkambotla, S., DuRand, I., Fullerton, D., Garg, S., Graham, C., Hartshorn, S., Hodgson, L., Jennings, P., Koshy, G., Leiner, T., Limb, J., Little, J., Matovu, E., McGill, F., Morris, C., Morrice, J., Price, D., Reschreiter, H., Reynolds, T., Whittaker, P., Tayler, R., Irving, C., Ramsay, M., Millar, M., Milligan, B., Hickey, N., Connon, M., Ward, C., Beveridge, L., MacFarlane, S., Leitch, K., Bell, C., Finlayson, L., Dawson, J., Candlish, J., McGenily, L., Roome, T., Diaba, C., Player, J., Powell, N., Howman, R., Burling, S., Floyd, S., Farmer, S., Ferguson, S., Hope, S., Rubick, L., Swingler, R., Collins, E., Spencer, C., Jones, A., Wilson, B., Armstrong, D., Birt, M., Dickinson, H., Harper, R., Martin, D., Roff, A., Mills, S., Martin, J., Ushiro-Lumb, I., Noursadeghi, M., Deheragoda, M., Hadzic, N., Grammatikopoulos, T., Brown, R., Kelgeri, C., Thalassinos, K., Waddington, S.N., Jacques, T.S., Levin, M., Brown, J.R., Breuer, J.
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Servizo Galego de Saúde (SERGAS)
Repositorio:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/21538
Acceso en línea:https://portalcientifico.sergas.gal//documentos/6473478ec0b3b1384998a572
http://hdl.handle.net/20.500.11940/21538
Access Level:acceso abierto
Palabra clave:Adenovirus Infections, Human
Gene Expression Profiling
Proteomics
B-Lymphocytes
Liver
Child
Acute Disease
Dependovirus
Hepatitis
T-Lymphocytes
Genomics
Humans
Immunohistochemistry
AS Santiago
CHUS
IDIS
Descripción
Sumario: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.