Biomarkers of sustained systemic inflammation and microvascular dysfunction associated with post-COVID-19 condition symptoms at 24 months after SARS-CoV-2-infection

Lotte M C Jacobs; Marieke S J N Wintjens; Magdolna Nagy; Loes Willems; Hugo Ten Cate; Henri M H Spronk; Sander M J van Kuijk; Chahinda Ghossein-Doha; Mihai G Netea; Laszlo A Groh; André S van Petersen; Michiel C Warlé

doi:10.3389/fimmu.2023.1182182

Biomarkers of sustained systemic inflammation and microvascular dysfunction associated with post-COVID-19 condition symptoms at 24 months after SARS-CoV-2-infection

Front Immunol. 2023 Oct 5:14:1182182. doi: 10.3389/fimmu.2023.1182182. eCollection 2023.

Authors

Lotte M C Jacobs¹, Marieke S J N Wintjens^{2

3}, Magdolna Nagy^{4

5}, Loes Willems¹, Hugo Ten Cate^{4

5

6

7}, Henri M H Spronk^{4

5

6}, Sander M J van Kuijk², Chahinda Ghossein-Doha^{5

8}, Mihai G Netea^{9

10}, Laszlo A Groh¹¹, André S van Petersen¹², Michiel C Warlé¹

Affiliations

¹ Department of Surgery, Radboud University Medical Center, Nijmegen, Netherlands.
² Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center+ (UMC+), Maastricht, Netherlands.
³ Department of Intensive Care Medicine, Maastricht University Medical Center+ (UMC+), Maastricht, Netherlands.
⁴ Department of Biochemistry, Maastricht University Medical Center+ (UMC+), Maastricht, Netherlands.
⁵ Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands.
⁶ Department of Internal Medicine, Maastricht University Medical Center+ (UMC+), Maastricht, Netherlands.
⁷ Center for Thrombosis and Haemostasis, Gutenberg University Medical Center, Mainz, Germany.
⁸ Department of Cardiology, Maastricht University Medical Center+ (UMC+), Maastricht, Netherlands.
⁹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
¹⁰ Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany.
¹¹ Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Institute for Infection and Immunity, Cancer Centre Amsterdam, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹² Department of Surgery, Bernhoven Hospital, Uden, Netherlands.

Abstract

Introduction: Comprehensive studies investigating sustained hypercoagulability, endothelial function, and/or inflammation in relation to post-COVID-19 (PCC) symptoms with a prolonged follow-up are currently lacking. Therefore, the aim of this single-centre cohort study was to investigate serum biomarkers of coagulation activation, microvascular dysfunction, and inflammation in relation to persisting symptoms two years after acute COVID-19.

Methods: Patients diagnosed with acute SARS-CoV-2 infection between February and June 2020 were recruited. Outcome measures included the CORona Follow-Up (CORFU) questionnaire, which is based on an internationally developed and partially validated basic questionnaire on persistent PCC symptoms. Additionally, plasma biomarkers reflecting coagulation activation, endothelial dysfunction and systemic inflammation were measured.

Results: 167 individuals were approached of which 148 (89%) completed the CORFU questionnaire. At 24 months after acute infection, fatigue was the most prevalent PCC symptom (84.5%). Over 50% of the patients experienced symptoms related to breathing, cognition, sleep or mobility; 30.3% still experienced at least one severe or extreme (4 or 5 on a 5-point scale) PCC symptom. Multiple correlations were found between several PCC symptoms and markers of endothelial dysfunction (endothelin-1 and von Willebrand factor) and systemic inflammation (Interleukin-1 Receptor antagonist). No positive correlations were found between PCC symptoms and coagulation complexes.

Discussion: In conclusion, this study shows that at 24 months after acute COVID-19 infection patients experience a high prevalence of PCC symptoms which correlate with inflammatory cytokine IL-1Ra and markers of endothelial dysfunction, especially endothelin-1. Our data may provide a rationale for the selection of treatment strategies for further clinical studies.

Trial registration: This study was performed in collaboration with the CORona Follow-Up (CORFU) study (NCT05240742, https://clinicaltrials.gov/ct2/show/ NCT05240742).

Keywords: SARS-CoV-2; coagulation activation; inflammation; microvascular dysfunction; post-COVID-19 condition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
COVID-19*
Cohort Studies
Endothelin-1
Humans
Inflammation
SARS-CoV-2

Substances

Endothelin-1
Biomarkers

Associated data

ClinicalTrials.gov/NCT05240742

Grants and funding

This work was partially funded by grants from The Netherlands Organization for Health Research and Development (grant numbers: 10430042010044 and 10430302110005).