Clinical utility of the neutrophil elastase inhibitor sivelestat for the treatment of ALI/ARDS patients with COVID-19

Abstract

Background: Sivelestat, a neutrophil elastase inhibitor, is postulated to mitigate acute lung injury in patients following emergency surgery. However, its efficacy in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) induced by coronavirus disease 2019 (COVID-19) remains uncertain. This study aims to evaluate the pulmonary protective effects of sivelestat in COVID-19 patients with ALI/ARDS.

Methods: A retrospective study was conducted involving 2454 COVID-19 patients between October 5, 2022, and February 1, 2023. Of these, 102 patients received sivelestat (0.2 mg/kg/h), while 2352 age- and sex-matched controls were identified. Propensity score matching (PSM) analysis was used to match sivelestat and non-sivelestat subgroups in ratios of 1:1 and 1:3 for sensitivity analysis. The primary outcome was a composite of effective outcomes, including 30-day mortality. Secondary outcomes included changes in partial pressure of arterial oxygen (PaO₂), the ratio of PaO₂ to the fraction of inspired oxygen (PaO₂/FiO₂), and various cytokine levels. Safety evaluations included assessments of liver function, kidney function, and leukopenia.

Results: In the propensity score-matched analysis, the sivelestat group had a higher proportion of severe/critical patients (87.26 % vs. 51.02 %, P < 0.001), more ARDS patients (4.9 % vs. 0.43 %, P < 0.001), and more patients with interstitial lung disease (4.9 % vs. 1.49 %, P = 0.023), but fewer patients with stroke (17.65 % vs. 19.86 %, P < 0.001). Oxygen therapy rates were similar between the groups (79.41 % vs. 80.95 %, P = 0.9). The relative risk reduction in 30-day mortality was 88.45 % (95 % confidence interval [CI] 81.23%-93.21 %) for severe/critical COVID-19 patients treated with sivelestat. Sivelestat significantly decreased cytokine levels of interferon alpha (IFNα), interleukin-1 beta (IL-1β), and interleukin-2 (IL-2).In the sivelestat group, the mortality rate was significantly reduced with standard oxygenation and HFNC therapy(P < 0.05). The treatment with sivelestat did not increase side effects.

Conclusion: The administration of the neutrophil elastase inhibitor sivelestat may improve clinical outcomes in COVID-19 patients with ALI/ARDS. These findings suggest that sivelestat could be considered an effective treatment option to alleviate pulmonary inflammatory injury caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Keywords: ARDS; COVID-19; Lung injury; Sivelestat; Treatment.

Fig. 1

Workflow of study design.

Fig. 2

Kaplan-Meier Plot of overall survival of sivelestat treatment. (A, B) PSM matched ratio 1:1 and 1:3 between sivelestat and non-sivelestat subgroups.

Fig. 3

Kaplan-Meier Plot of overall survival of patients receiving oxygen therapy. (A, B) PSM matched ratio 1:1 and 1:3 between sivelestat and non-sivelestat subgroups.

Fig. 4

Kaplan-Meier Plot of survival of patients with different severity levels. (A, B) A illustrates the comparison of survival rates among patients with moderate COVID-19; Figure B presents the comparison of survival rates among patients with severe and critical COVID-19.

Fig. 5

Kaplan-Meier Plot of survival of patients with different Different oxygen treatments.Figure A represents patients treated with invasive ventilators; Figure B with non-invasive ventilators; Figure C with nasal cannula/mask oxygenation; Figure D with high-flow oxygen therapy. (Note: Duration in Fig A and B is reduced due to classification based on the highest level of respiratory support.).

Fig. 6

Barplot of all samples. Clinical and laboratory parameters'comparison between Treatment and Control group. Here, one can observe that some cytokines such as IFNα、IL-1β and IL-2 decreased significantly in sivelestat group than that in Control group, whereas Others cytokine did not differ significantly between both groups.(*P < 0.05,**P < 0.01,***P < 0.001).Fig. 6A. Barplots of matched samples by ratio 1:1 Fig. 6B. Barplots of matched samples by ratio 1:3.