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

Felicity Liew; Claudia Efstathiou; Sara Fontanella; Matthew Richardson; Ruth Saunders; Dawid Swieboda; Jasmin K. Sidhu; Stephanie Ascough; Shona C. Moore; Noura Mohamed; Jose Nunag; Clara King; Olivia C. Leavy; Omer Elneima; Hamish J. C. McAuley; Aarti Shikotra; Amisha Singapuri; Marco Sereno; Victoria C. Harris; Linzy Houchen-Wolloff; Neil J. Greening; Nazir I. Lone; Matthew Thorpe; A. A. Roger Thompson; Sarah L. Rowland-Jones; Annemarie B. Docherty; James D. Chalmers; Ling-Pei Ho; Alexander Horsley; Betty Raman; Krisnah Poinasamy; Michael Marks; Onn Min Kon; Luke S. Howard; Daniel G. Wootton; Jennifer K. Quint; Thushan I. de Silva; Antonia Ho; Christopher Chiu; Ewen M. Harrison; William Greenhalf; J. Kenneth Baillie; Malcolm G. Semple; Lance Turtle; Rachael A. Evans; Louise V. Wain; Christopher Brightling; Ryan S. Thwaites; Peter J. M. Openshaw; PHOSP-COVID Collaborative Group; Ioannis Vogiatzis; 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, Claudia Efstathiou, Sara Fontanella, Matthew Richardson, Ruth Saunders, Dawid Swieboda, Jasmin K. Sidhu, Stephanie Ascough, Shona C. Moore, Noura Mohamed, Jose Nunag, Clara King, Olivia C. Leavy, Omer Elneima, Hamish J. C. McAuley, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Victoria C. Harris, Linzy Houchen-WolloffNeil J. Greening, Nazir I. Lone, Matthew Thorpe, A. A. Roger Thompson, Sarah L. Rowland-Jones, Annemarie B. Docherty, James D. Chalmers, Ling-Pei Ho, Alexander Horsley, Betty Raman, Krisnah Poinasamy, Michael Marks, Onn Min Kon, Luke S. Howard, Daniel G. Wootton, Jennifer K. Quint, Thushan I. de Silva, Antonia Ho, Christopher Chiu, Ewen M. Harrison, William Greenhalf, J. Kenneth Baillie, Malcolm G. Semple, Lance Turtle, Rachael A. Evans, Louise V. Wain, Christopher Brightling, Ryan S. Thwaites^*, Peter J. M. Openshaw^*, PHOSP-COVID Collaborative Group, Ioannis Vogiatzis, ISARIC investigators

^*Corresponding author for this work

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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
Early online date	8 Apr 2024
DOIs	https://doi.org/10.1038/s41590-024-01778-0
Publication status	Published - Apr 2024

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Cite this

Liew, F., Efstathiou, C., Fontanella, S., Richardson, M., Saunders, R., Swieboda, D., Sidhu, J. K., Ascough, S., Moore, S. C., Mohamed, N., Nunag, J., King, C., Leavy, O. C., Elneima, O., McAuley, H. J. C., Shikotra, A., Singapuri, A., Sereno, M., Harris, V. C., ... 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

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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.",

author = "Felicity Liew and Claudia Efstathiou and Sara Fontanella and Matthew Richardson and Ruth Saunders and Dawid Swieboda and Sidhu, {Jasmin K.} and Stephanie Ascough and Moore, {Shona C.} and Noura Mohamed and Jose Nunag and Clara King and Leavy, {Olivia C.} and Omer Elneima and McAuley, {Hamish J. C.} and Aarti Shikotra and Amisha Singapuri and Marco Sereno and Harris, {Victoria C.} and Linzy Houchen-Wolloff and Greening, {Neil J.} and Lone, {Nazir I.} and Matthew Thorpe and Thompson, {A. A. Roger} and Rowland-Jones, {Sarah L.} and Docherty, {Annemarie B.} and Chalmers, {James D.} and Ling-Pei Ho and Alexander Horsley and Betty Raman and Krisnah Poinasamy and Michael Marks and Kon, {Onn Min} and Howard, {Luke S.} and Wootton, {Daniel G.} and Quint, {Jennifer K.} and {de Silva}, {Thushan I.} and Antonia Ho and Christopher Chiu and Harrison, {Ewen M.} and William Greenhalf and Baillie, {J. Kenneth} and Semple, {Malcolm G.} and Lance Turtle and Evans, {Rachael A.} and Wain, {Louise V.} and Christopher Brightling and Thwaites, {Ryan S.} and Openshaw, {Peter J. M.} and {PHOSP-COVID Collaborative Group} and Ioannis Vogiatzis 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",

publisher = "Nature Publishing Group",

number = "4",

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Liew, F, Efstathiou, C, Fontanella, S, Richardson, M, Saunders, R, Swieboda, D, Sidhu, JK, Ascough, S, Moore, SC, Mohamed, N, Nunag, J, King, C, Leavy, OC, Elneima, O, McAuley, HJC, Shikotra, A, Singapuri, A, Sereno, M, Harris, VC, Houchen-Wolloff, L, Greening, NJ, Lone, NI, Thorpe, M, Thompson, AAR, Rowland-Jones, SL, Docherty, AB, Chalmers, JD, Ho, L-P, Horsley, A, Raman, B, Poinasamy, K, Marks, M, Kon, OM, Howard, LS, Wootton, DG, Quint, JK, de Silva, TI, Ho, A, Chiu, C, Harrison, EM, Greenhalf, W, Baillie, JK, Semple, MG, Turtle, L, Evans, RA, Wain, LV, Brightling, C, Thwaites, RS, Openshaw, PJM, PHOSP-COVID Collaborative Group, Vogiatzis, I & 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 - Efstathiou, Claudia

AU - Fontanella, Sara

AU - Richardson, Matthew

AU - Saunders, Ruth

AU - Swieboda, Dawid

AU - Sidhu, Jasmin K.

AU - Ascough, Stephanie

AU - Moore, Shona C.

AU - Mohamed, Noura

AU - Nunag, Jose

AU - King, Clara

AU - Leavy, Olivia C.

AU - Elneima, Omer

AU - McAuley, Hamish J. C.

AU - Shikotra, Aarti

AU - Singapuri, Amisha

AU - Sereno, Marco

AU - Harris, Victoria C.

AU - Houchen-Wolloff, Linzy

AU - Greening, Neil J.

AU - Lone, Nazir I.

AU - Thorpe, Matthew

AU - Thompson, A. A. Roger

AU - Rowland-Jones, Sarah L.

AU - Docherty, Annemarie B.

AU - Chalmers, James D.

AU - Ho, Ling-Pei

AU - Horsley, Alexander

AU - Raman, Betty

AU - Poinasamy, Krisnah

AU - Marks, Michael

AU - Kon, Onn Min

AU - Howard, Luke S.

AU - Wootton, Daniel G.

AU - Quint, Jennifer K.

AU - de Silva, Thushan I.

AU - Ho, Antonia

AU - Chiu, Christopher

AU - Harrison, Ewen M.

AU - Greenhalf, William

AU - Baillie, J. Kenneth

AU - Semple, Malcolm G.

AU - Turtle, Lance

AU - Evans, Rachael A.

AU - Wain, Louise V.

AU - Brightling, Christopher

AU - Thwaites, Ryan S.

AU - Openshaw, Peter J. M.

AU - PHOSP-COVID Collaborative Group

AU - Vogiatzis, Ioannis

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.

U2 - 10.1038/s41590-024-01778-0

DO - 10.1038/s41590-024-01778-0

M3 - Letter

SN - 1529-2908

VL - 25

SP - 607

EP - 621

JO - Nature Immunology

JF - Nature Immunology

IS - 4

ER -