Journal Article

Molecular mechanisms and treatment responses of pulmonary fibrosis in severe COVID-19

Gerretsen, Jelle, Kooistra, Emma J., Kox, Matthijs, Ulas, Thomas, Nuesch Germano, Melanie, Smeets, Ruben L., Schultze, Joachim L., van den Berg, Maarten J. W., van Herwaarden, Antonius E., Pickkers, Peter, Mauer, Karoline, van der Hoeven, Johannes G., Aschenbrenner, Anna C., van der Velde, Sjef, Dahm, Kilian

2023

Overview

Background Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. Methods We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA - (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. Results Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4 , PDE4D , MMP8 , CRISP3 , and BCL2L15 . Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay ( pre-DEXA : 42 [29–49] vs. 18 [13–27] days, p < 0.001; DEXA : 42 [28–57] vs. 13 [7–24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes. Conclusions ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Acute respiratory distress syndrome / Analysis / Biological markers / Biomarkers / Care and treatment / Clinical outcomes / Coagulation / Cohort analysis / Coronavirus disease 2019 / Coronaviruses / COVID-19 / Cytokines / Dexamethasone / Diagnosis / Disease Progression / Dosage and administration / Drug dosages / Dual energy X-ray absorptiometry / Fibrosis / Gene sequencing / Genes / Health services / Humans / Idiopathic Pulmonary Fibrosis / Inflammation / Leukocytes / Leukocytes (neutrophilic) / Lung diseases / Medicine / Medicine & Public Health / Molecular mechanics / Molecular modelling / Mortality / Neutrophil collagenase / Parameter identification / Patients / Phosphodiesterase / Pneumology/Respiratory System / Prednisone / Protein-arginine deiminase / Pulmonary fibrosis / Respiration, Artificial / RNA sequencing / SARS-CoV-2 / Statistical analysis / Steroids / Transcriptomes / Transcriptomics / Ventilation / Ventilators / Viral diseases