| Title: |
Adeno-associated virus 2 infection in children with non-A-E hepatitis |
| Authors: |
Ho, A.; Orton, R.; Tayler, R.; Asamaphan, P.; Herder, V.; Davis, C.; Tong, L.; Smollett, K.; Manali, M.; Allan, J.; Rawlik, K.; McDonald, S.E.; Vink, E.; Pollock, L.; Gannon, L.; Evans, C.; McMenamin, J.; Roy, K.; Marsh, K.; Divala, T.; Holden, M.T.G.; Lockhart, M.; Yirrell, D.; Currie, S.; O'Leary, M.; Henderson, D.; Shepherd, S.J.; Jackson, C.; Gunson, R.; MacLean, A.; McInnes, N.; Bradley-Stewart, A.; Battle, R.; Hollenbach, J.A.; Henderson, P.; Odam, M.; Chikowore, P.; Oosthuyzen, W.; Chand, M.; Hamilton, M.S.; Estrada-Rivadeneyra, D.; Levin, M.; Avramidis, N.; Pairo-Castineira, E.; Vitart, V.; Wilkie, C.; Cunnington, A.; Herberg, J.; Kaforou, M.; Wright, V.; Bellos, E.; Broderick, C.; Channon-Wells, S.; Cooray, S.; De, T.; D'Souza, G.; Elorrieta, L.E.; Galassini, R.; Habgood-Coote, D.; Jackson, H.; Kavanagh, J.; Marjaneh, M.M.; Menikou, S.; Nichols, S.; Nijman, R.; Patel, H.; Pennisi, I.; Powell, O.; Reid, R.; Shah, P.; 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, M.; 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.; O'Neill, L.; 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.; Anthony, M.; 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, A.; González, F.Á.; Bello, X.; Ben García, M.; 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.; Sánchez, J.M.M.; Pérez, B.M.; 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.; Newall, 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.; Wallia, D.; 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.W.T.; van de Kuip, M.M.; van Furth, A.M.M.; van den Berg, J.M.M.; Biesbroek, G.; Verkuil, F.; van der Zee, C.C.W.; Pajkrt, D.; van Hensbroek, M.B.; Schonenberg, D.; Gruppen, M.; Nagelkerke, S.; Jansen, M.H.; Goetschalckx, I.; Romani, L.; De Luca, M.; Chiurchiù, S.; Di Giuseppe, M.; Vermont, C.L.; Moll, H.A.; Borensztajn, D.M.; Hagedoorn, N.N.; Tan, C.; Zachariasse, J.; students, M.; Dik, W.; Shen, C.-F.K.; 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.; Av?in, T.; Avramoska, T.; Bahovec, N.; Bogovi?, P.; Kitanovski, L.; Nahtigal, M.; Papst, L.; Srovin, T.P.; Strle, F.; Srp?i?, 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.; Meier, M.; Weber, K.; Schlapbach, L.J.; 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.; Fink, C.; Voice, M.; Calvo-Bado, L.; Steele, M.; Holden, J.; 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.; Momodou, S.; Usuf, E.; Ndure, E.; Bojang, K.; Roca, A.; Sarr, I.; Semple, M.G.; Carson, G.; Openshaw, P.J.M.; Dunning, J.; Merson, L.; Russell, C.D.; Dorward, D.; Zambon, M.; Tedder, R.S.; Khoo, S.; Turtle, L.C.W.; Solomon, T.; Ijaz, S.; Fletcher, T.; Thomson, E.C.; Price, N.; Breuer, J.; de Silva, T.; Donohue, C.; Hardwick, H.; Obosi, L.; Clohisey, S.; Law, A.; Norris, L.; Tait, S.; Wham, M.; Clark, R.; Coutts, A.; Donnelly, L.; Fawkes, A.; Gilchrist, T.; Hafezi, K.; MacGillivray, L.; Maclean, A.; McCafferty, S.; Morrice, K.; Murphy, L.; Wrobel, N.; Shaw, V.; Ahmed, K.A.; Armstrong, J.A.; Lett, L.; Kishore, S.; Brotherton, H.; Armstrong, L.; Mitra, A.; Dall, A.; Bohmova, K.; Logan, S.; Agwuh, K.; Chukkambotla, S.; DuRand, I.; Fullerton, D.; Gar, S.; Graham, C.; Grammatikopoulos, T.; 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.; Jordan, T.; Irving, C.; Jack, K.; 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.; Palmarini, M.; Ray, S.; Robertson, D.L.; da Silva Filipe, A.; Willett, B.J.; Turner, D.; Baillie, J.K. |
| Publication Year: |
2023 |
| Subject Terms: |
Child; Humans; Acute Disease; Adenovirus Infections; Human; Alleles; Case-Control Studies; CD4-Positive T-Lymphocytes; Coinfection; Dependovirus; Genetic Predisposition to Disease; Helper Viruses; Hepatitis; Hepatocytes; HLA-DRB1 Chains; Liver; AS Santiago; CHUS; IDIS |
| Description: |
An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 in April 2022 and has now been identified in 35 countries 2. 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. ; We wish to acknowledge the contribution of the participating children and their parents who agreed to participate in the ISARIC CCP-UK and DIAMONDS studies, and the research teams who recruited the patients; S.Bennett-Slater from NHS Greater Glasgow and Clyde for assisting with sample location and testing; the histopathology team, Veterinary Diagnostic, University of Glasgow, for excellent technical assistance; P.Murcia for providing resources and advice; P.Olmo for administrative assistance; and E.J.Kremer from the Institut de Genetique Moleculaire de Montpellier, Universite de Montpellier and A.Baker, University of Edinburgh, for ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Public Health Scotland; National Institute for Health Research (NIHR) [CO-CIN-01]; Medical Research Council (MRC) [MR/X010252/1, MC_UU_1201412, MC_UU_12018/12, MC_PC_19059, MC_PC_19025, MC_PC_22004]; European Union [848196]; Wellcome Trust [206369/Z/17/Z]; NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool; UK Health Security Agency; Wellcome Trust Senior Research Fellowship [223164/Z/21/Z, MC_PC_20029]; BBSRC Institute Strategic Programme Grant [BB/P013732/1, BB/P013759/1]; Intensive Care Society of the United Kingdom; Pandemic Institute, Liverpool and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool; University of Edinburgh; UK Biobank Resource [788, 26041]; National Institute for Health and Care Research [CO-CIN-01]; NIHR [MC_PC_19059, CV220-169]; UK Research and Innovation [MC_PC_19059, CV220-169]; NHS Research Scotland (NRS); Medical Research Council [MC_UU_12014/1, MC_PC_19059, MC_UU_12014/12, MC_UU_00007/10] Funding Source: researchfish; National Institute for Health Research [NIHR200224] Funding Source: researchfish; COVID [MR/W005611/1, MC_PC_19025, MC_PC_19059] Funding Source: UKRI; MRC [MC_UU_12014/1, MC_PC_22004, MR/W030454/1, MC_UU_00007/10, MC_UU_00034/5, MC_UU_00034/6, MR/X010252/1] Funding Source: UKRI; https://doi.org/10.1038/s41586-023-05948-2; https://portalcientifico.sergas.gal//documentos/64860188a219857f1d78b6f5; https://hdl.handle.net/20.500.11940/21025; 64860188a219857f1d78b6f5 |
| DOI: |
10.1038/s41586-023-05948-2 |
| Availability: |
https://hdl.handle.net/20.500.11940/21025; https://portalcientifico.sergas.gal//documentos/64860188a219857f1d78b6f5; https://doi.org/10.1038/s41586-023-05948-2 |
| Rights: |
Attribution 4.0 International (CC BY 4.0) ; http://creativecommons.org/licenses/by/4.0/ ; openAccess |
| Accession Number: |
edsbas.2B4B82CB |
| Database: |
BASE |