Adeno-associated virus 2 infection in children with non-A-E hepatitis

ISARIC4C Investigators; Antonia Ho; Richard Orton; Rachel Tayler; Patawee Asamaphan; Vanessa Herder; Chris Davis; Lily Tong; Katherine Smollett; Maria Manali; Jay Allan; Konrad Rawlik; Sarah E. McDonald; Elen Vink; Louisa Pollock; Louise Gannon; Clair Evans; Jim McMenamin; Kirsty Roy; Kimberly Marsh; Titus Divala; Matthew T. G. Holden; Michael Lockhart; David Yirrell; Sandra Currie; Maureen O'Leary; David Henderson; Samantha J. Shepherd; Celia Jackson; Rory Gunson; Alasdair MacLean; Neil McInnes; Amanda Bradley-Stewart; Richard Battle; Jill Hollenbach; Paul Henderson; Miranda Odam; Primrose Chikowore; Wilna Oosthuyzen; Meera Chand; Melissa Shea Hamilton; Diego Estrada-Rivadeneyra; Michael Levin; Nikos Avramidis; Erola Pairo-Castineira; Veronique Vitart; Craig Wilkie; Massimo Palmarini; Surajit Ray; David L. Robertson; Ana da Silva Filipe; Brian J. Willett; Judith Breuer; Malcolm G. Semple; David Turner; J. Kenneth Baillie; Emma C. Thomson

doi:10.1038/s41586-023-05948-2

Adeno-associated virus 2 infection in children with non-A-E hepatitis

, ISARIC4C Investigators, Antonia Ho, Richard Orton, Rachel Tayler, Patawee Asamaphan, Vanessa Herder, Chris Davis, Lily Tong, Katherine Smollett, Maria Manali, Jay Allan, Konrad Rawlik, Sarah E. McDonald, Elen Vink, Louisa Pollock, Louise Gannon, Clair Evans, Jim McMenamin, Kirsty RoyKimberly Marsh, Titus Divala, Matthew T. G. Holden, Michael Lockhart, David Yirrell, Sandra Currie, Maureen O'Leary, David Henderson, Samantha J. Shepherd, Celia Jackson, Rory Gunson, Alasdair MacLean, Neil McInnes, Amanda Bradley-Stewart, Richard Battle, Jill Hollenbach, Paul Henderson, Miranda Odam, Primrose Chikowore, Wilna Oosthuyzen, Meera Chand, Melissa Shea Hamilton, Diego Estrada-Rivadeneyra, Michael Levin, Nikos Avramidis, Erola Pairo-Castineira, Veronique Vitart, Craig Wilkie, Massimo Palmarini, Surajit Ray, David L. Robertson, Ana da Silva Filipe, Brian J. Willett, Judith Breuer, Malcolm G. Semple, David Turner, J. Kenneth Baillie, Emma C. Thomson (Lead / Corresponding author)

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Abstract

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.

Original language	English
Pages (from-to)	555–563
Number of pages	9
Journal	Nature
Volume	617
Issue number	7961
Early online date	30 Mar 2023
DOIs	https://doi.org/10.1038/s41586-023-05948-2
Publication status	Published - 18 May 2023

Keywords

Viral genetics
Virology

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41586-023-05948-2

Author Accepted ManuscriptAccepted author manuscript, 34.8 MBLicence: CC BY

Cite this

, ISARIC4C Investigators, 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., ... Thomson, E. C. (2023). Adeno-associated virus 2 infection in children with non-A-E hepatitis. Nature, 617(7961), 555–563. https://doi.org/10.1038/s41586-023-05948-2

@article{e61ffc5f05a24b71aa86ad1e02d225a8,

title = "Adeno-associated virus 2 infection in children with non-A-E hepatitis",

abstract = "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 {\textquoteleft}helper virus{\textquoteright} to support AAV2 replication) and disease susceptibility related to HLA class II status.",

keywords = "Viral genetics, Virology",

author = "{ISARIC4C Investigators} and Antonia Ho and Richard Orton and Rachel Tayler and Patawee Asamaphan and Vanessa Herder and Chris Davis and Lily Tong and Katherine Smollett and Maria Manali and Jay Allan and Konrad Rawlik and McDonald, {Sarah E.} and Elen Vink and Louisa Pollock and Louise Gannon and Clair Evans and Jim McMenamin and Kirsty Roy and Kimberly Marsh and Titus Divala and Holden, {Matthew T. G.} and Michael Lockhart and David Yirrell and Sandra Currie and Maureen O'Leary and David Henderson and Shepherd, {Samantha J.} and Celia Jackson and Rory Gunson and Alasdair MacLean and Neil McInnes and Amanda Bradley-Stewart and Richard Battle and Jill Hollenbach and Paul Henderson and Miranda Odam and Primrose Chikowore and Wilna Oosthuyzen and Meera Chand and Hamilton, {Melissa Shea} and Diego Estrada-Rivadeneyra and Michael Levin and Nikos Avramidis and Erola Pairo-Castineira and Veronique Vitart and Craig Wilkie and Massimo Palmarini and Surajit Ray and Robertson, {David L.} and {da Silva Filipe}, Ana and Willett, {Brian J.} and Judith Breuer and Semple, {Malcolm G.} and David Turner and Baillie, {J. Kenneth} and Thomson, {Emma C.}",

note = "Funding Information: 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 G{\'e}n{\'e}tique Mol{\'e}culaire de Montpellier, Universit{\'e} de Montpellier and A. Baker, University of Edinburgh, for advice. The work was funded by Public Health Scotland, the National Institute for Health Research (NIHR; award CO-CIN-01) and the Medical Research Council (MRC; grants MR/X010252/1, MC_UU_1201412, MC_UU_12018/12, MC_PC_19059, MC_PC_19025 and MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). M.P. acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). M.G.S. acknowledges funding support from The Pandemic Institute, Liverpool and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and UK Health Security Agency. J.K.B. acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Programme Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the Intensive Care Society of the United Kingdom. We acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. Parts of this research has been conducted using the UK Biobank Resource under project 788 and we would like to acknowledge the assistance of A. Tenesa in making this possible. Additional replication was also conducted using the UK Biobank Resource (Project 26041). This research was also funded by the National Institute for Health and Care Research (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). The views expressed in this article are those of the author(s) and not necessarily those of UKRI, the NIHR, or the Department of Health and Social Care. We also acknowledge the support of NHS Research Scotland (NRS) Greater Glasgow and Clyde Biorepository team. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = may,

day = "18",

doi = "10.1038/s41586-023-05948-2",

language = "English",

volume = "617",

pages = "555–563",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

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ISARIC4C Investigators, Ho, A, Orton, R, Tayler, R, Asamaphan, P, Herder, V, Davis, C, Tong, L, Smollett, K, Manali, M, Allan, J, Rawlik, K, McDonald, SE, Vink, E, Pollock, L, Gannon, L, Evans, C, McMenamin, J, Roy, K, Marsh, K, Divala, T, Holden, MTG, Lockhart, M, Yirrell, D, Currie, S, O'Leary, M, Henderson, D, Shepherd, SJ, Jackson, C, Gunson, R, MacLean, A, McInnes, N, Bradley-Stewart, A, Battle, R, Hollenbach, J, Henderson, P, Odam, M, Chikowore, P, Oosthuyzen, W, Chand, M, Hamilton, MS, Estrada-Rivadeneyra, D, Levin, M, Avramidis, N, Pairo-Castineira, E, Vitart, V, Wilkie, C, Palmarini, M, Ray, S, Robertson, DL, da Silva Filipe, A, Willett, BJ, Breuer, J, Semple, MG, Turner, D & Baillie, JK & Thomson, EC 2023, 'Adeno-associated virus 2 infection in children with non-A-E hepatitis', Nature, vol. 617, no. 7961, pp. 555–563. https://doi.org/10.1038/s41586-023-05948-2

TY - JOUR

T1 - Adeno-associated virus 2 infection in children with non-A-E hepatitis

AU - ISARIC4C Investigators

AU - Ho, Antonia

AU - Orton, Richard

AU - Tayler, Rachel

AU - Asamaphan, Patawee

AU - Herder, Vanessa

AU - Davis, Chris

AU - Tong, Lily

AU - Smollett, Katherine

AU - Manali, Maria

AU - Allan, Jay

AU - Rawlik, Konrad

AU - McDonald, Sarah E.

AU - Vink, Elen

AU - Pollock, Louisa

AU - Gannon, Louise

AU - Evans, Clair

AU - McMenamin, Jim

AU - Roy, Kirsty

AU - Marsh, Kimberly

AU - Divala, Titus

AU - Holden, Matthew T. G.

AU - Lockhart, Michael

AU - Yirrell, David

AU - Currie, Sandra

AU - O'Leary, Maureen

AU - Henderson, David

AU - Shepherd, Samantha J.

AU - Jackson, Celia

AU - Gunson, Rory

AU - MacLean, Alasdair

AU - McInnes, Neil

AU - Bradley-Stewart, Amanda

AU - Battle, Richard

AU - Hollenbach, Jill

AU - Henderson, Paul

AU - Odam, Miranda

AU - Chikowore, Primrose

AU - Oosthuyzen, Wilna

AU - Chand, Meera

AU - Hamilton, Melissa Shea

AU - Estrada-Rivadeneyra, Diego

AU - Levin, Michael

AU - Avramidis, Nikos

AU - Pairo-Castineira, Erola

AU - Vitart, Veronique

AU - Wilkie, Craig

AU - Palmarini, Massimo

AU - Ray, Surajit

AU - Robertson, David L.

AU - da Silva Filipe, Ana

AU - Willett, Brian J.

AU - Breuer, Judith

AU - Semple, Malcolm G.

AU - Turner, David

AU - Baillie, J. Kenneth

AU - Thomson, Emma C.

N1 - Funding Information: 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 Génétique Moléculaire de Montpellier, Université de Montpellier and A. Baker, University of Edinburgh, for advice. The work was funded by Public Health Scotland, the National Institute for Health Research (NIHR; award CO-CIN-01) and the Medical Research Council (MRC; grants MR/X010252/1, MC_UU_1201412, MC_UU_12018/12, MC_PC_19059, MC_PC_19025 and MC_PC_22004). DIAMONDS is funded by the European Union Horizon 2020 programme; grant 848196). M.P. acknowledges funding support from the Wellcome Trust (206369/Z/17/Z). M.G.S. acknowledges funding support from The Pandemic Institute, Liverpool and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and UK Health Security Agency. J.K.B. acknowledges funding support from a Wellcome Trust Senior Research Fellowship (223164/Z/21/Z), and MC_PC_20029, Sepsis Research (Fiona Elizabeth Agnew Trust), a BBSRC Institute Strategic Programme Grant to the Roslin Institute (BB/P013732/1, BB/P013759/1), and the Intensive Care Society of the United Kingdom. We acknowledge the support of Baillie Gifford and the Baillie Gifford Science Pandemic Hub at the University of Edinburgh. Parts of this research has been conducted using the UK Biobank Resource under project 788 and we would like to acknowledge the assistance of A. Tenesa in making this possible. Additional replication was also conducted using the UK Biobank Resource (Project 26041). This research was also funded by the National Institute for Health and Care Research (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). The views expressed in this article are those of the author(s) and not necessarily those of UKRI, the NIHR, or the Department of Health and Social Care. We also acknowledge the support of NHS Research Scotland (NRS) Greater Glasgow and Clyde Biorepository team. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/5/18

Y1 - 2023/5/18

N2 - 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.

AB - 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.

KW - Viral genetics

KW - Virology

UR - http://www.scopus.com/inward/record.url?scp=85159304324&partnerID=8YFLogxK

U2 - 10.1038/s41586-023-05948-2

DO - 10.1038/s41586-023-05948-2

M3 - Article

C2 - 36996873

SN - 0028-0836

VL - 617

SP - 555

EP - 563

JO - Nature

JF - Nature

IS - 7961

ER -

Adeno-associated virus 2 infection in children with non-A-E hepatitis

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