Genomic investigations of unexplained acute hepatitis in children

Sofia Morfopoulou; Sarah Buddle; Oscar Enrique Torres Montaguth; Laura Atkinson; José Afonso Guerra-Assunção; Mahdi Moradi Marjaneh; Riccardo Zenezini Chiozzi; Nathaniel Storey; Luis Campos; J. Ciaran Hutchinson; John R. Counsell; Gabriele Pollara; Sunando Roy; Cristina Venturini; Juan F. Antinao Diaz; Ala’a Siam; Luke J. Tappouni; Zeinab Asgarian; Joanne Ng; Killian S. Hanlon; Alexander Lennon; Andrew McArdle; Agata Czap; Joshua Rosenheim; Catarina Andrade; Glenn Anderson; Jack C. D. Lee; Rachel Williams; Charlotte A. Williams; Helena Tutill; Nadua Bayzid; Luz Marina Martin Bernal; Hannah Macpherson; Kylie-Ann Montgomery; Catherine Moore; Kate Templeton; Claire Neill; Matt Holden; Rory Gunson; Samantha J. Shepherd; Priyen Shah; Samantha Cooray; Marie Voice; Michael Steele; Colin Fink; Thomas E. Whittaker; Giorgia Santilli; Paul Gissen; Benedikt B. Kaufer; Jana Reich; DIAMONDS consortium; ISARIC 4C Investigators; PERFORM Consortium; Judith Breuer

doi:10.1038/s41586-023-06003-w

Genomic investigations of unexplained acute hepatitis in children

Sofia Morfopoulou, Sarah Buddle, Oscar Enrique Torres Montaguth, Laura Atkinson, José Afonso Guerra-Assunção, Mahdi Moradi Marjaneh, Riccardo Zenezini Chiozzi, Nathaniel Storey, Luis Campos, J. Ciaran Hutchinson, John R. Counsell, Gabriele Pollara, Sunando Roy, Cristina Venturini, Juan F. Antinao Diaz, Ala’a Siam, Luke J. Tappouni, Zeinab Asgarian, Joanne Ng, Killian S. HanlonAlexander Lennon, Andrew McArdle, Agata Czap, Joshua Rosenheim, Catarina Andrade, Glenn Anderson, Jack C. D. Lee, Rachel Williams, Charlotte A. Williams, Helena Tutill, Nadua Bayzid, Luz Marina Martin Bernal, Hannah Macpherson, Kylie-Ann Montgomery, Catherine Moore, Kate Templeton, Claire Neill, Matt Holden, Rory Gunson, Samantha J. Shepherd, Priyen Shah, Samantha Cooray, Marie Voice, Michael Steele, Colin Fink, Thomas E. Whittaker, Giorgia Santilli, Paul Gissen, Benedikt B. Kaufer, Jana Reich, DIAMONDS consortium, ISARIC 4C Investigators, PERFORM Consortium, Judith Breuer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK¹. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded 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 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.

Original language	English
Pages (from-to)	564-592
Number of pages	29
Journal	Nature
Volume	617
Early online date	30 Mar 2023
DOIs	https://doi.org/10.1038/s41586-023-06003-w
Publication status	Published - 18 May 2023

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Genomic investigations of unexplained acute hepatitis in children (code)
Holden, M. (Creator), GitHub, 2023
https://github.com/sarah-buddle/unknown-hepatitis and one more link, https://github.com/MahdiMoradiMarjaneh/proteomics_and_transcriptomics_of_hepatitis (show fewer)
Dataset: Software

Cite this

Morfopoulou, S., Buddle, S., Montaguth, O. E. T., Atkinson, L., Guerra-Assunção, J. A., Marjaneh, M. M., Chiozzi, R. Z., 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., ... Breuer, J. (2023). Genomic investigations of unexplained acute hepatitis in children. Nature, 617, 564-592. https://doi.org/10.1038/s41586-023-06003-w

@article{e7f39ea930cb446499134eef08c05704,

title = "Genomic investigations of unexplained acute hepatitis in children",

abstract = "Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded 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 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.",

author = "Sofia Morfopoulou and Sarah Buddle and Montaguth, {Oscar Enrique Torres} and Laura Atkinson and Guerra-Assun{\c c}{\~a}o, {Jos{\'e} Afonso} and Marjaneh, {Mahdi Moradi} and Chiozzi, {Riccardo Zenezini} and Nathaniel Storey and Luis Campos and Hutchinson, {J. Ciaran} and Counsell, {John R.} and Gabriele Pollara and Sunando Roy and Cristina Venturini and {Antinao Diaz}, {Juan F.} and Ala{\textquoteright}a Siam and Tappouni, {Luke J.} and Zeinab Asgarian and Joanne Ng and Hanlon, {Killian S.} and Alexander Lennon and Andrew McArdle and Agata Czap and Joshua Rosenheim and Catarina Andrade and Glenn Anderson and Lee, {Jack C. D.} and Rachel Williams and Williams, {Charlotte A.} and Helena Tutill and Nadua Bayzid and Bernal, {Luz Marina Martin} and Hannah Macpherson and Kylie-Ann Montgomery and Catherine Moore and Kate Templeton and Claire Neill and Matt Holden and Rory Gunson and Shepherd, {Samantha J.} and Priyen Shah and Samantha Cooray and Marie Voice and Michael Steele and Colin Fink and Whittaker, {Thomas E.} and Giorgia Santilli and Paul Gissen and Kaufer, {Benedikt B.} and Jana Reich and {DIAMONDS consortium} and {ISARIC 4C Investigators} and {PERFORM Consortium} and Judith Breuer",

note = "Funding: UKHSA funded the metagenomics and HAdV sequencing. The work was part funded by the NIHR Blood and Transplant Research Unit in Genomics to Enhance Microbiology Screening (GEMS), the National Institute for Health and Care Research (CO-CIN-01) or jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). S. Morfopoulou is funded by a W.T. Henry Wellcome fellowship (206478/Z/17/Z). S.B. and O.E.T.M. are funded by the NIHR Blood and Transplant Research Unit (GEMS). M.M.M. and M.L. are supported in part by the NIHR Biomedical Research Centre of Imperial College NHS Trust. J.B. receives NIHR Senior Investigator Funding. M.N. and J.B. are supported by the Wellcome Trust (207511/Z/17/Z and 203268/Z/16/Z). M.N., J.B. and G.P. are supported by the NIHR University College London Hospitals Biomedical Research Centre. P. Simmonds is supported by the NIHR (NIHR203338). T.S.J. is grateful for funding from the Brain Tumour Charity, Children with Cancer UK, GOSH Children{\textquoteright}s Charity, Olivia Hodson Cancer Fund, Cancer Research UK and the NIHR. DIAMONDS is funded by the European Union (Horizon 2020; grant 848196). PERFORM was funded by the European Union (Horizon 2020; grant 668303).",

year = "2023",

month = may,

day = "18",

doi = "10.1038/s41586-023-06003-w",

language = "English",

volume = "617",

pages = "564--592",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature publishing group",

}

Morfopoulou, S, Buddle, S, Montaguth, OET, Atkinson, L, Guerra-Assunção, JA, Marjaneh, MM, Chiozzi, RZ, Storey, N, Campos, L, Hutchinson, JC, Counsell, JR, Pollara, G, Roy, S, Venturini, C, Antinao Diaz, JF, Siam, A, Tappouni, LJ, Asgarian, Z, Ng, J, Hanlon, KS, Lennon, A, McArdle, A, Czap, A, Rosenheim, J, Andrade, C, Anderson, G, Lee, JCD, Williams, R, Williams, CA, Tutill, H, Bayzid, N, Bernal, LMM, Macpherson, H, Montgomery, K-A, Moore, C, Templeton, K, Neill, C, Holden, M, Gunson, R, Shepherd, SJ, Shah, P, Cooray, S, Voice, M, Steele, M, Fink, C, Whittaker, TE, Santilli, G, Gissen, P, Kaufer, BB, Reich, J, DIAMONDS consortium, ISARIC 4C Investigators, PERFORM Consortium & Breuer, J 2023, 'Genomic investigations of unexplained acute hepatitis in children', Nature, vol. 617, pp. 564-592. https://doi.org/10.1038/s41586-023-06003-w

TY - JOUR

T1 - Genomic investigations of unexplained acute hepatitis in children

AU - Morfopoulou, Sofia

AU - Buddle, Sarah

AU - Montaguth, Oscar Enrique Torres

AU - Atkinson, Laura

AU - Guerra-Assunção, José Afonso

AU - Marjaneh, Mahdi Moradi

AU - Chiozzi, Riccardo Zenezini

AU - Storey, Nathaniel

AU - Campos, Luis

AU - Hutchinson, J. Ciaran

AU - Counsell, John R.

AU - Pollara, Gabriele

AU - Roy, Sunando

AU - Venturini, Cristina

AU - Antinao Diaz, Juan F.

AU - Siam, Ala’a

AU - Tappouni, Luke J.

AU - Asgarian, Zeinab

AU - Ng, Joanne

AU - Hanlon, Killian S.

AU - Lennon, Alexander

AU - McArdle, Andrew

AU - Czap, Agata

AU - Rosenheim, Joshua

AU - Andrade, Catarina

AU - Anderson, Glenn

AU - Lee, Jack C. D.

AU - Williams, Rachel

AU - Williams, Charlotte A.

AU - Tutill, Helena

AU - Bayzid, Nadua

AU - Bernal, Luz Marina Martin

AU - Macpherson, Hannah

AU - Montgomery, Kylie-Ann

AU - Moore, Catherine

AU - Templeton, Kate

AU - Neill, Claire

AU - Holden, Matt

AU - Gunson, Rory

AU - Shepherd, Samantha J.

AU - Shah, Priyen

AU - Cooray, Samantha

AU - Voice, Marie

AU - Steele, Michael

AU - Fink, Colin

AU - Whittaker, Thomas E.

AU - Santilli, Giorgia

AU - Gissen, Paul

AU - Kaufer, Benedikt B.

AU - Reich, Jana

AU - DIAMONDS consortium

AU - ISARIC 4C Investigators

AU - PERFORM Consortium

AU - Breuer, Judith

N1 - Funding: UKHSA funded the metagenomics and HAdV sequencing. The work was part funded by the NIHR Blood and Transplant Research Unit in Genomics to Enhance Microbiology Screening (GEMS), the National Institute for Health and Care Research (CO-CIN-01) or jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). S. Morfopoulou is funded by a W.T. Henry Wellcome fellowship (206478/Z/17/Z). S.B. and O.E.T.M. are funded by the NIHR Blood and Transplant Research Unit (GEMS). M.M.M. and M.L. are supported in part by the NIHR Biomedical Research Centre of Imperial College NHS Trust. J.B. receives NIHR Senior Investigator Funding. M.N. and J.B. are supported by the Wellcome Trust (207511/Z/17/Z and 203268/Z/16/Z). M.N., J.B. and G.P. are supported by the NIHR University College London Hospitals Biomedical Research Centre. P. Simmonds is supported by the NIHR (NIHR203338). T.S.J. is grateful for funding from the Brain Tumour Charity, Children with Cancer UK, GOSH Children’s Charity, Olivia Hodson Cancer Fund, Cancer Research UK and the NIHR. DIAMONDS is funded by the European Union (Horizon 2020; grant 848196). PERFORM was funded by the European Union (Horizon 2020; grant 668303).

PY - 2023/5/18

Y1 - 2023/5/18

N2 - Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded 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 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.

AB - Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded 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 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.

U2 - 10.1038/s41586-023-06003-w

DO - 10.1038/s41586-023-06003-w

M3 - Article

C2 - 36996872

SN - 0028-0836

VL - 617

SP - 564

EP - 592

JO - Nature

JF - Nature

ER -

Genomic investigations of unexplained acute hepatitis in children

Abstract

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Genomic investigations of unexplained acute hepatitis in children (code)

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