Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

Felicity  Liew; David Anderson; Cherie Armour; Natalie Armstrong; R. E. Barker; M. Beggs; M. Begum; Robert Bell; Vanessa Brown; M. Brown; J. Brown; M. Brown; Jeremy Brown; G. Burns; A. Burns; John Busby; S. Byrne; P. Cairns; G. Carson; Anna Casey; Jin Chen; Bronwen Connolly; B. Cooper; Thelma Craig; Melanie Davies; S. L. Dobson; Stephen Drain; K. Elliott; D. Evans; R. Evans; K. Fallon; S. Fletcher; X. Fu; J. George; D. Grieve; Neil Hanley; Liam Heaney; C. Johnson; S. Jones; H. Jones; L. Jones; Mark Jones; S. Kelly; X. Li; M. Marshall; B. Marshall; L. M. Martinez; W. McCormick; P. McCourt; Lorcan McGarvey; I. B. McInnes; Michael McMahon; J. McNeill; C. A. Miller; Clare Mills; L. Milner; S. Mohammed; C. M. Nolan; J. Owen; M. Pavlides; Tunde Peto; L. Price; D. Price; L. Price; M. Richardson; Emma Robinson; M. J. Rowland; Emily Russell; Janet T. Scott; Kathryn Scott; M. Sharma; Salman Siddiqui; David Smith; Susan Smith; S. Thomas; S. Walker; Simon Walsh; J. A. Walsh; T. J.C. Ward; L. Watson; C. Wright; S. Wright; A. Young; Siddharth Bakshi; Gail Carson; Christopher Davis; Christopher B. Jones; Mark Lyttle; Patrick Morgan; Michael Murphy; Janet T. Scott; Catherine A. Shaw; Richard Smith; Zoltan Takats; PHOSP-COVID Study Collaborative Group; ISARIC investigators

doi:10.1038/s41590-024-01778-0

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

Felicity Liew, David Anderson, Cherie Armour, Natalie Armstrong, R. E. Barker, M. Beggs, M. Begum, Robert Bell, Vanessa Brown, M. Brown, J. Brown, M. Brown, Jeremy Brown, G. Burns, A. Burns, John Busby, S. Byrne, P. Cairns, G. Carson, Anna CaseyJin Chen, Bronwen Connolly, B. Cooper, Thelma Craig, Melanie Davies, S. L. Dobson, Stephen Drain, K. Elliott, D. Evans, R. Evans, K. Fallon, S. Fletcher, X. Fu, J. George, D. Grieve, Neil Hanley, Liam Heaney, C. Johnson, S. Jones, H. Jones, L. Jones, Mark Jones, S. Kelly, X. Li, M. Marshall, B. Marshall, L. M. Martinez, W. McCormick, P. McCourt, Lorcan McGarvey, I. B. McInnes, Michael McMahon, J. McNeill, C. A. Miller, Clare Mills, L. Milner, S. Mohammed, C. M. Nolan, J. Owen, M. Pavlides, Tunde Peto, L. Price, D. Price, L. Price, M. Richardson, Emma Robinson, M. J. Rowland, Emily Russell, Janet T. Scott, Kathryn Scott, M. Sharma, Salman Siddiqui, David Smith, Susan Smith, S. Thomas, S. Walker, Simon Walsh, J. A. Walsh, T. J.C. Ward, L. Watson, C. Wright, S. Wright, A. Young, Siddharth Bakshi, Gail Carson, Christopher Davis, Christopher B. Jones, Mark Lyttle, Patrick Morgan, Michael Murphy, Janet T. Scott, Catherine A. Shaw, Richard Smith, Zoltan Takats, PHOSP-COVID Study Collaborative Group, ISARIC investigators

School of Medicine, Dentistry and Biomedical Sciences

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

12 Citations (Scopus)

Abstract

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood¹. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Original language	English
Pages (from-to)	607-621
Number of pages	15
Journal	Nature Immunology
Volume	25
Issue number	4
DOIs	https://doi.org/10.1038/s41590-024-01778-0
Publication status	Published - Apr 2024

Keywords

phenotyping
COVID
disease
long COVID

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease
Copyright 2024 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 14.5 MBLicence: CC BY

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Liew, F., Anderson, D., Armour, C., Armstrong, N., Barker, R. E., Beggs, M., Begum, M., Bell, R., Brown, V., Brown, M., Brown, J., Brown, M., Brown, J., Burns, G., Burns, A., Busby, J., Byrne, S., Cairns, P., Carson, G., ... ISARIC investigators (2024). Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease. Nature Immunology, 25(4), 607-621. https://doi.org/10.1038/s41590-024-01778-0

@article{1fae95c4cd244669b2530e1cb246b4f8,

title = "Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease",

abstract = "One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.",

keywords = "phenotyping, COVID, disease, long COVID",

author = "Felicity Liew and David Anderson and Cherie Armour and Natalie Armstrong and Barker, {R. E.} and M. Beggs and M. Begum and Robert Bell and Vanessa Brown and M. Brown and J. Brown and M. Brown and Jeremy Brown and G. Burns and A. Burns and John Busby and S. Byrne and P. Cairns and G. Carson and Anna Casey and Jin Chen and Bronwen Connolly and B. Cooper and Thelma Craig and Melanie Davies and Dobson, {S. L.} and Stephen Drain and K. Elliott and D. Evans and R. Evans and K. Fallon and S. Fletcher and X. Fu and J. George and D. Grieve and Neil Hanley and Liam Heaney and C. Johnson and S. Jones and H. Jones and L. Jones and Mark Jones and S. Kelly and X. Li and M. Marshall and B. Marshall and Martinez, {L. M.} and W. McCormick and P. McCourt and Lorcan McGarvey and McInnes, {I. B.} and Michael McMahon and J. McNeill and Miller, {C. A.} and Clare Mills and L. Milner and S. Mohammed and Nolan, {C. M.} and J. Owen and M. Pavlides and Tunde Peto and L. Price and D. Price and L. Price and M. Richardson and Emma Robinson and Rowland, {M. J.} and Emily Russell and Scott, {Janet T.} and Kathryn Scott and M. Sharma and Salman Siddiqui and David Smith and Susan Smith and S. Thomas and S. Walker and Simon Walsh and Walsh, {J. A.} and Ward, {T. J.C.} and L. Watson and C. Wright and S. Wright and A. Young and Siddharth Bakshi and Gail Carson and Christopher Davis and Jones, {Christopher B.} and Mark Lyttle and Patrick Morgan and Michael Murphy and Scott, {Janet T.} and Shaw, {Catherine A.} and Richard Smith and Zoltan Takats and {PHOSP-COVID Study Collaborative Group} and {ISARIC investigators}",

year = "2024",

month = apr,

doi = "10.1038/s41590-024-01778-0",

language = "English",

volume = "25",

pages = "607--621",

journal = "Nature Immunology",

issn = "1529-2908",

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Liew, F, Anderson, D, Armour, C, Armstrong, N, Barker, RE, Beggs, M, Begum, M, Bell, R, Brown, V, Brown, M, Brown, J, Brown, M, Brown, J, Burns, G, Burns, A, Busby, J, Byrne, S, Cairns, P, Carson, G, Casey, A, Chen, J, Connolly, B, Cooper, B, Craig, T, Davies, M, Dobson, SL, Drain, S, Elliott, K, Evans, D, Evans, R, Fallon, K, Fletcher, S, Fu, X, George, J, Grieve, D, Hanley, N, Heaney, L, Johnson, C, Jones, S, Jones, H, Jones, L, Jones, M, Kelly, S, Li, X, Marshall, M, Marshall, B, Martinez, LM, McCormick, W, McCourt, P, McGarvey, L, McInnes, IB, McMahon, M, McNeill, J, Miller, CA, Mills, C, Milner, L, Mohammed, S, Nolan, CM, Owen, J, Pavlides, M, Peto, T, Price, L, Price, D, Price, L, Richardson, M, Robinson, E, Rowland, MJ, Russell, E, Scott, JT, Scott, K, Sharma, M, Siddiqui, S, Smith, D, Smith, S, Thomas, S, Walker, S, Walsh, S, Walsh, JA, Ward, TJC, Watson, L, Wright, C, Wright, S, Young, A, Bakshi, S, Carson, G, Davis, C, Jones, CB, Lyttle, M, Morgan, P, Murphy, M, Scott, JT, Shaw, CA, Smith, R, Takats, Z, PHOSP-COVID Study Collaborative Group & ISARIC investigators 2024, 'Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease', Nature Immunology, vol. 25, no. 4, pp. 607-621. https://doi.org/10.1038/s41590-024-01778-0

TY - JOUR

T1 - Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

AU - Liew, Felicity

AU - Anderson, David

AU - Armour, Cherie

AU - Armstrong, Natalie

AU - Barker, R. E.

AU - Beggs, M.

AU - Begum, M.

AU - Bell, Robert

AU - Brown, Vanessa

AU - Brown, M.

AU - Brown, J.

AU - Brown, M.

AU - Brown, Jeremy

AU - Burns, G.

AU - Burns, A.

AU - Busby, John

AU - Byrne, S.

AU - Cairns, P.

AU - Carson, G.

AU - Casey, Anna

AU - Chen, Jin

AU - Connolly, Bronwen

AU - Cooper, B.

AU - Craig, Thelma

AU - Davies, Melanie

AU - Dobson, S. L.

AU - Drain, Stephen

AU - Elliott, K.

AU - Evans, D.

AU - Evans, R.

AU - Fallon, K.

AU - Fletcher, S.

AU - Fu, X.

AU - George, J.

AU - Grieve, D.

AU - Hanley, Neil

AU - Heaney, Liam

AU - Johnson, C.

AU - Jones, S.

AU - Jones, H.

AU - Jones, L.

AU - Jones, Mark

AU - Kelly, S.

AU - Li, X.

AU - Marshall, M.

AU - Marshall, B.

AU - Martinez, L. M.

AU - McCormick, W.

AU - McCourt, P.

AU - McGarvey, Lorcan

AU - McInnes, I. B.

AU - McMahon, Michael

AU - McNeill, J.

AU - Miller, C. A.

AU - Mills, Clare

AU - Milner, L.

AU - Mohammed, S.

AU - Nolan, C. M.

AU - Owen, J.

AU - Pavlides, M.

AU - Peto, Tunde

AU - Price, L.

AU - Price, D.

AU - Price, L.

AU - Richardson, M.

AU - Robinson, Emma

AU - Rowland, M. J.

AU - Russell, Emily

AU - Scott, Janet T.

AU - Scott, Kathryn

AU - Sharma, M.

AU - Siddiqui, Salman

AU - Smith, David

AU - Smith, Susan

AU - Thomas, S.

AU - Walker, S.

AU - Walsh, Simon

AU - Walsh, J. A.

AU - Ward, T. J.C.

AU - Watson, L.

AU - Wright, C.

AU - Wright, S.

AU - Young, A.

AU - Bakshi, Siddharth

AU - Carson, Gail

AU - Davis, Christopher

AU - Jones, Christopher B.

AU - Lyttle, Mark

AU - Morgan, Patrick

AU - Murphy, Michael

AU - Scott, Janet T.

AU - Shaw, Catherine A.

AU - Smith, Richard

AU - Takats, Zoltan

AU - PHOSP-COVID Study Collaborative Group

AU - ISARIC investigators

PY - 2024/4

Y1 - 2024/4

N2 - One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

AB - One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

KW - phenotyping

KW - COVID

KW - disease

KW - long COVID

U2 - 10.1038/s41590-024-01778-0

DO - 10.1038/s41590-024-01778-0

M3 - Letter

C2 - 38589621

AN - SCOPUS:85190085946

SN - 1529-2908

VL - 25

SP - 607

EP - 621

JO - Nature Immunology

JF - Nature Immunology

IS - 4

ER -

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

Abstract

Keywords

ASJC Scopus subject areas

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