TY - JOUR
T1 - Extracellular matrix turnover in severe COVID-19 is reduced by corticosteroids
AU - Pillay, Janesh
AU - Flikweert, Antine W
AU - van Meurs, Matijs
AU - Grootenboers, Marco J
AU - van der Sar-van der Brugge, Simone
AU - van der Voort, Peter H J
AU - Karsdal, Morten A
AU - Sand, Jannie M B
AU - Leeming, Diana J
AU - Burgess, Janette K
AU - Moser, Jill
N1 - © 2025. The Author(s).
PY - 2025/1/22
Y1 - 2025/1/22
N2 - BACKGROUND: Severe and critical COVID-19 is characterized by pulmonary viral infection with SARS-CoV-2 resulting in local and systemic inflammation. Dexamethasone (DEX) has been shown to improve outcomes in critically ill patients; however, its effect on tissue remodeling, particularly collagen turnover, remains unclear. This study investigated the association between circulating extracellular matrix (ECM) remodeling neo-epitopes and COVID-19 severity, their relationship with mortality, and the effect of DEX on these markers.METHODS: We conducted a multi-center prospective cohort study involving 226 COVID-19 patients: 157 with severe disease admitted to the ward and 69 with critical disease admitted to the ICU. Plasma samples were collected at ICU admission and at discharge or death. Circulating collagen degradation (C3M, C4Ma3, and C6M) and synthesis (PRO-C3, PRO-C4, and PRO-C6) neo-epitopes were measured. Longitudinal analysis of ECM neo-epitope changes during ICU stay and their association with mortality was performed, along with an evaluation of the impact of DEX treatment on these markers.RESULTS: Critically ill patients exhibited higher levels of collagen degradation (reflecting inflammatory driven ECM destruction) (C3M, C6M) and collagen synthesis (strongly related to fibroblast activity) (PRO-C3, PRO-C6) neo-epitopes than severe patients. Increased collagen turnover, measured during ICU stay, was associated with mortality. Non-survivors displayed rising levels of collagen degradation and synthesis markers over time, whereas survivors had stable or declining levels. In non-survivors without DEX treatment, C6M and PRO-C6 levels were significantly increased, whereas these elevations were less pronounced in patients treated with DEX.CONCLUSION: Our findings suggest that elevated collagen turnover is associated with poor outcomes in critically ill COVID-19 patients. DEX treatment appeared to attenuate ECM remodeling, although this effect was not linked to improved survival. Further studies are needed to confirm these observations and better understand the role of ECM remodeling in COVID-19 and the potential therapeutic impact of corticosteroids.
AB - BACKGROUND: Severe and critical COVID-19 is characterized by pulmonary viral infection with SARS-CoV-2 resulting in local and systemic inflammation. Dexamethasone (DEX) has been shown to improve outcomes in critically ill patients; however, its effect on tissue remodeling, particularly collagen turnover, remains unclear. This study investigated the association between circulating extracellular matrix (ECM) remodeling neo-epitopes and COVID-19 severity, their relationship with mortality, and the effect of DEX on these markers.METHODS: We conducted a multi-center prospective cohort study involving 226 COVID-19 patients: 157 with severe disease admitted to the ward and 69 with critical disease admitted to the ICU. Plasma samples were collected at ICU admission and at discharge or death. Circulating collagen degradation (C3M, C4Ma3, and C6M) and synthesis (PRO-C3, PRO-C4, and PRO-C6) neo-epitopes were measured. Longitudinal analysis of ECM neo-epitope changes during ICU stay and their association with mortality was performed, along with an evaluation of the impact of DEX treatment on these markers.RESULTS: Critically ill patients exhibited higher levels of collagen degradation (reflecting inflammatory driven ECM destruction) (C3M, C6M) and collagen synthesis (strongly related to fibroblast activity) (PRO-C3, PRO-C6) neo-epitopes than severe patients. Increased collagen turnover, measured during ICU stay, was associated with mortality. Non-survivors displayed rising levels of collagen degradation and synthesis markers over time, whereas survivors had stable or declining levels. In non-survivors without DEX treatment, C6M and PRO-C6 levels were significantly increased, whereas these elevations were less pronounced in patients treated with DEX.CONCLUSION: Our findings suggest that elevated collagen turnover is associated with poor outcomes in critically ill COVID-19 patients. DEX treatment appeared to attenuate ECM remodeling, although this effect was not linked to improved survival. Further studies are needed to confirm these observations and better understand the role of ECM remodeling in COVID-19 and the potential therapeutic impact of corticosteroids.
KW - Humans
KW - Male
KW - Female
KW - COVID-19/mortality
KW - Extracellular Matrix/metabolism
KW - Middle Aged
KW - Prospective Studies
KW - Aged
KW - Dexamethasone/therapeutic use
KW - COVID-19 Drug Treatment
KW - Critical Illness
KW - Severity of Illness Index
KW - Cohort Studies
KW - Adrenal Cortex Hormones/therapeutic use
KW - Collagen/metabolism
KW - Intensive Care Units
UR - http://www.scopus.com/inward/record.url?scp=85216608149&partnerID=8YFLogxK
U2 - 10.1186/s12931-025-03098-9
DO - 10.1186/s12931-025-03098-9
M3 - Article
C2 - 39844140
SN - 1465-9921
VL - 26
JO - Respiratory Research
JF - Respiratory Research
IS - 1
M1 - 32
ER -