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

Abstract

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.

Integrating fecal metabolomics and intestinal microbiota to study the mechanism of cannabidiol in the treatment of idiopathic pulmonary fibrosis

“…Additionally, biochemical analysis demonstrated a notable elevation in the levels of hydroxyproline. Prednisone, a hormone-based pharmaceutical commonly used for the clinical treatment of IPF ( Kooistra et al, 2023 ), was employed as the reference drug in numerous previous animal studies investigating IPF. Our findings indicate that there was no significant disparity between the high-dose CBD group and the positive control group in terms of their capacity to enhance lung permeability and ameliorate the pathological alterations observed in rats with IPF.…”

Long-Term Radiological Pulmonary Changes in Mechanically Ventilated Patients with Respiratory Failure due to SARS-CoV-2 Infection

“…They also proved that early dexamethasone treatment did not influence the severity or the incidence of pulmonary fibrosis. Instead, prednisone treatment initiated in patients with early suspicion of pulmonary fibrosis (both from the group on dexamethasone treatment and from the group that did not receive dexamethasone) was correlated with the reduction of fibrosis biomarkers and specific genes (matrix metalloproteinase 8 [MMP8], phosphodiesterase 4D [PDE4D], cysteine-rich secretory protein [CRISP3], B-cell lymphoma 2 like protein 15 [BCL2L15] that were previously upregulated towards those observed in non-pulmonary fibrosis group [124]. Other studies to prevent pulmonary fibrosis suggest that inhibitors of upregulated genes (MMP8, PDE4) in patients with pulmonary fibrosis might be a therapeutic target [124][125][126].…”

Post COVID-19 Pulmonary Fibrosis Management: A Systematic Review

“…Factors like chronic comorbidities, female sex, older age and the use of mechanical ventilation have all been associated with an increased risk [11]. The treatment of pulmonary fibrosis nowadays is corticosteroids; however, this is for non-COVID-19 ARDS patients [12]. Many different managements have been tried for the purpose of treating PC-19-PF.…”