Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response

P4O2 Consortium; Jelle M. Blankestijn; Nadia Baalbaki; Somayeh Bazdar; Inés Beekers; Rosanne J.H.C.G. Beijers; Joop P. van den Bergh; Lizan D. Bloemsma; Merel E.B. Cornelissen; Tamara Dekker; Jan Willem Duitman; Laura Houweling; John J.L. Jacobs; Ivo van der Lee; Paulien M.A. Linders; Lieke C.E. Noij; Esther J. Nossent; Marianne A. van de Pol; Brigitte M. Sondermeijer; J. J.Miranda Geelhoed; Els J.M. Weersink; Korneliusz Golebski; Mahmoud I. Abdel-Aziz; Anke H. Maitland-van der Zee

doi:10.1016/j.jaci.2024.04.032

Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response

P4O2 Consortium
, Jelle M. Blankestijn^*
, Nadia Baalbaki
, Somayeh Bazdar
, Inés Beekers
, Rosanne J.H.C.G. Beijers
, Joop P. van den Bergh
, Lizan D. Bloemsma
, Merel E.B. Cornelissen
, Tamara Dekker
, Jan Willem Duitman
, Laura Houweling
, John J.L. Jacobs
, Ivo van der Lee
, Paulien M.A. Linders
, Lieke C.E. Noij
, Esther J. Nossent
, Marianne A. van de Pol
, Brigitte M. Sondermeijer
, J. J.Miranda Geelhoed

Els J.M. Weersink, Korneliusz Golebski, Mahmoud I. Abdel-Aziz, Anke H. Maitland-van der Zee

^*Corresponding author for this work

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

Abstract

Background: Months after infection with severe acute respiratory syndrome coronavirus 2, at least 10% of patients still experience complaints. Long-COVID (coronavirus disease 2019) is a heterogeneous disease, and clustering efforts revealed multiple phenotypes on a clinical level. However, the molecular pathways underlying long-COVID phenotypes are still poorly understood. Objectives: We sought to cluster patients according to their blood transcriptomes and uncover the pathways underlying their disease. Methods: Blood was collected from 77 patients with long-COVID from the Precision Medicine for more Oxygen (P4O2) COVID-19 study. Unsupervised hierarchical clustering was performed on the whole blood transcriptome. These clusters were analyzed for differences in clinical features, pulmonary function tests, and gene ontology term enrichment. Results: Clustering revealed 2 distinct clusters on a transcriptome level. Compared with cluster 2 (n = 65), patients in cluster 1 (n = 12) showed a higher rate of preexisting cardiovascular disease (58% vs 22%), higher prevalence of gastrointestinal symptoms (58% vs 29%), shorter hospital duration during severe acute respiratory syndrome coronavirus 2 infection (median, 3 vs 8 days), lower FEV₁/forced vital capacity (72% vs 81%), and lower diffusion capacity of the lung for carbon monoxide (68% vs 85% predicted). Gene ontology term enrichment analysis revealed upregulation of genes involved in the antiviral innate immune response in cluster 1, whereas genes involved with the adaptive immune response were upregulated in cluster 2. Conclusions: This study provides a start in uncovering the pathophysiological mechanisms underlying long-COVID. Further research is required to unravel why the immune response is different in these clusters, and to identify potential therapeutic targets to create an optimized treatment or monitoring strategy for the individual long-COVID patient.

Original language	English
Pages (from-to)	807-818
Number of pages	12
Journal	Journal of Allergy and Clinical Immunology
Volume	154
Issue number	3
Early online date	1 Jun 2024
DOIs	https://doi.org/10.1016/j.jaci.2024.04.032
Publication status	Published - Sept 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Funding

Ingelheim and Abbvie. M. I. Abdel-Aziz was funded by a full PhD scholarship from the Ministry of Higher Education of the Arab Republic of Egypt during the conduct of the study and received a grant from Stichting Astma Bestrijding. A. H. Maitland-van der Zee received money paid to the institution from the ERANET Systems Medicine and ZonMW grant, another ZonMW grant for COVID-19 research, the Stichting TAAI research grant, the EUROSTARS research grant COPDetect, an unrestricted research grant from Boehringer Ingelheim and GSK, an unrestricted research grant from the Vertex Innovation Award, and the Innovative Health Initiative 3TR research grant; is the (unpaid) chair of the DSMB SOS BPD study; and was the president of the federation of innovative drug research in the Netherlands (FIGON) . The rest of the authors declare that they have no relevant conflicts of interest.

Funders
Abbvie - Ministry of Higher Education of the Arab Republic of Egypt
Stichting Astma Bestrijding
ERANET Systems Medicine and ZonMW grant
Stichting TAAI research grant
EUROSTARS research grant COPDetect
Boehringer Ingelheim
Vertex Innovation Award
Innovative Health Initiative 3TR research grant
president of the federation of innovative drug research in the Netherlands

Keywords

DLCO
Long-COVID
lung function
phenotyping
transcriptome

UN SDGs

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

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10.1016/j.jaci.2024.04.032Licence: CC BY

PIIS0091674924005669Final published version, 2.48 MBLicence: CC BY

Cite this

P4O2 Consortium, Blankestijn, J. M., Baalbaki, N., Bazdar, S., Beekers, I., Beijers, R. J. H. C. G., van den Bergh, J. P., Bloemsma, L. D., Cornelissen, M. E. B., Dekker, T., Duitman, J. W., Houweling, L., Jacobs, J. J. L., van der Lee, I., Linders, P. M. A., Noij, L. C. E., Nossent, E. J., van de Pol, M. A., Sondermeijer, B. M., ... Maitland-van der Zee, A. H. (2024). Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response. Journal of Allergy and Clinical Immunology, 154(3), 807-818. https://doi.org/10.1016/j.jaci.2024.04.032

@article{59f11f135763428a8704e8774397c4b1,

title = "Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response",

abstract = "Background: Months after infection with severe acute respiratory syndrome coronavirus 2, at least 10\% of patients still experience complaints. Long-COVID (coronavirus disease 2019) is a heterogeneous disease, and clustering efforts revealed multiple phenotypes on a clinical level. However, the molecular pathways underlying long-COVID phenotypes are still poorly understood. Objectives: We sought to cluster patients according to their blood transcriptomes and uncover the pathways underlying their disease. Methods: Blood was collected from 77 patients with long-COVID from the Precision Medicine for more Oxygen (P4O2) COVID-19 study. Unsupervised hierarchical clustering was performed on the whole blood transcriptome. These clusters were analyzed for differences in clinical features, pulmonary function tests, and gene ontology term enrichment. Results: Clustering revealed 2 distinct clusters on a transcriptome level. Compared with cluster 2 (n = 65), patients in cluster 1 (n = 12) showed a higher rate of preexisting cardiovascular disease (58\% vs 22\%), higher prevalence of gastrointestinal symptoms (58\% vs 29\%), shorter hospital duration during severe acute respiratory syndrome coronavirus 2 infection (median, 3 vs 8 days), lower FEV1/forced vital capacity (72\% vs 81\%), and lower diffusion capacity of the lung for carbon monoxide (68\% vs 85\% predicted). Gene ontology term enrichment analysis revealed upregulation of genes involved in the antiviral innate immune response in cluster 1, whereas genes involved with the adaptive immune response were upregulated in cluster 2. Conclusions: This study provides a start in uncovering the pathophysiological mechanisms underlying long-COVID. Further research is required to unravel why the immune response is different in these clusters, and to identify potential therapeutic targets to create an optimized treatment or monitoring strategy for the individual long-COVID patient.",

keywords = "DLCO, Long-COVID, lung function, phenotyping, transcriptome",

author = "\{P4O2 Consortium\} and Blankestijn, \{Jelle M.\} and Nadia Baalbaki and Somayeh Bazdar and In{\'e}s Beekers and Beijers, \{Rosanne J.H.C.G.\} and \{van den Bergh\}, \{Joop P.\} and Bloemsma, \{Lizan D.\} and Cornelissen, \{Merel E.B.\} and Tamara Dekker and Duitman, \{Jan Willem\} and Laura Houweling and Jacobs, \{John J.L.\} and \{van der Lee\}, Ivo and Linders, \{Paulien M.A.\} and Noij, \{Lieke C.E.\} and Nossent, \{Esther J.\} and \{van de Pol\}, \{Marianne A.\} and Sondermeijer, \{Brigitte M.\} and Geelhoed, \{J. J.Miranda\} and Weersink, \{Els J.M.\} and Korneliusz Golebski and Abdel-Aziz, \{Mahmoud I.\} and \{Maitland-van der Zee\}, \{Anke H.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = sep,

doi = "10.1016/j.jaci.2024.04.032",

language = "English",

volume = "154",

pages = "807--818",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "3",

}

P4O2 Consortium, Blankestijn, JM, Baalbaki, N, Bazdar, S, Beekers, I, Beijers, RJHCG, van den Bergh, JP, Bloemsma, LD, Cornelissen, MEB, Dekker, T, Duitman, JW, Houweling, L, Jacobs, JJL, van der Lee, I, Linders, PMA, Noij, LCE, Nossent, EJ, van de Pol, MA, Sondermeijer, BM, Geelhoed, JJM, Weersink, EJM, Golebski, K, Abdel-Aziz, MI & Maitland-van der Zee, AH 2024, 'Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response', Journal of Allergy and Clinical Immunology, vol. 154, no. 3, pp. 807-818. https://doi.org/10.1016/j.jaci.2024.04.032

TY - JOUR

T1 - Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response

AU - P4O2 Consortium

AU - Blankestijn, Jelle M.

AU - Baalbaki, Nadia

AU - Bazdar, Somayeh

AU - Beekers, Inés

AU - Beijers, Rosanne J.H.C.G.

AU - van den Bergh, Joop P.

AU - Bloemsma, Lizan D.

AU - Cornelissen, Merel E.B.

AU - Dekker, Tamara

AU - Duitman, Jan Willem

AU - Houweling, Laura

AU - Jacobs, John J.L.

AU - van der Lee, Ivo

AU - Linders, Paulien M.A.

AU - Noij, Lieke C.E.

AU - Nossent, Esther J.

AU - van de Pol, Marianne A.

AU - Sondermeijer, Brigitte M.

AU - Geelhoed, J. J.Miranda

AU - Weersink, Els J.M.

AU - Golebski, Korneliusz

AU - Abdel-Aziz, Mahmoud I.

AU - Maitland-van der Zee, Anke H.

PY - 2024/9

Y1 - 2024/9

N2 - Background: Months after infection with severe acute respiratory syndrome coronavirus 2, at least 10% of patients still experience complaints. Long-COVID (coronavirus disease 2019) is a heterogeneous disease, and clustering efforts revealed multiple phenotypes on a clinical level. However, the molecular pathways underlying long-COVID phenotypes are still poorly understood. Objectives: We sought to cluster patients according to their blood transcriptomes and uncover the pathways underlying their disease. Methods: Blood was collected from 77 patients with long-COVID from the Precision Medicine for more Oxygen (P4O2) COVID-19 study. Unsupervised hierarchical clustering was performed on the whole blood transcriptome. These clusters were analyzed for differences in clinical features, pulmonary function tests, and gene ontology term enrichment. Results: Clustering revealed 2 distinct clusters on a transcriptome level. Compared with cluster 2 (n = 65), patients in cluster 1 (n = 12) showed a higher rate of preexisting cardiovascular disease (58% vs 22%), higher prevalence of gastrointestinal symptoms (58% vs 29%), shorter hospital duration during severe acute respiratory syndrome coronavirus 2 infection (median, 3 vs 8 days), lower FEV1/forced vital capacity (72% vs 81%), and lower diffusion capacity of the lung for carbon monoxide (68% vs 85% predicted). Gene ontology term enrichment analysis revealed upregulation of genes involved in the antiviral innate immune response in cluster 1, whereas genes involved with the adaptive immune response were upregulated in cluster 2. Conclusions: This study provides a start in uncovering the pathophysiological mechanisms underlying long-COVID. Further research is required to unravel why the immune response is different in these clusters, and to identify potential therapeutic targets to create an optimized treatment or monitoring strategy for the individual long-COVID patient.

AB - Background: Months after infection with severe acute respiratory syndrome coronavirus 2, at least 10% of patients still experience complaints. Long-COVID (coronavirus disease 2019) is a heterogeneous disease, and clustering efforts revealed multiple phenotypes on a clinical level. However, the molecular pathways underlying long-COVID phenotypes are still poorly understood. Objectives: We sought to cluster patients according to their blood transcriptomes and uncover the pathways underlying their disease. Methods: Blood was collected from 77 patients with long-COVID from the Precision Medicine for more Oxygen (P4O2) COVID-19 study. Unsupervised hierarchical clustering was performed on the whole blood transcriptome. These clusters were analyzed for differences in clinical features, pulmonary function tests, and gene ontology term enrichment. Results: Clustering revealed 2 distinct clusters on a transcriptome level. Compared with cluster 2 (n = 65), patients in cluster 1 (n = 12) showed a higher rate of preexisting cardiovascular disease (58% vs 22%), higher prevalence of gastrointestinal symptoms (58% vs 29%), shorter hospital duration during severe acute respiratory syndrome coronavirus 2 infection (median, 3 vs 8 days), lower FEV1/forced vital capacity (72% vs 81%), and lower diffusion capacity of the lung for carbon monoxide (68% vs 85% predicted). Gene ontology term enrichment analysis revealed upregulation of genes involved in the antiviral innate immune response in cluster 1, whereas genes involved with the adaptive immune response were upregulated in cluster 2. Conclusions: This study provides a start in uncovering the pathophysiological mechanisms underlying long-COVID. Further research is required to unravel why the immune response is different in these clusters, and to identify potential therapeutic targets to create an optimized treatment or monitoring strategy for the individual long-COVID patient.

KW - DLCO

KW - Long-COVID

KW - lung function

KW - phenotyping

KW - transcriptome

UR - https://www.scopus.com/pages/publications/85197581983

U2 - 10.1016/j.jaci.2024.04.032

DO - 10.1016/j.jaci.2024.04.032

M3 - Article

C2 - 38830512

AN - SCOPUS:85197581983

SN - 0091-6749

VL - 154

SP - 807

EP - 818

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

Whole blood transcriptome in long-COVID patients reveals association with lung function and immune response

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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