Non-Randomized Trial of Dornase Alfa for Acute Respiratory Distress Syndrome Secondary to Covid-19

Abstract

Background: The most severe cases of Coronavirus-Disease-2019 (COVID-19) develop into Acute Respiratory Distress Syndrome (ARDS). It has been proposed that oxygenation may be inhibited by extracellular deoxyribonucleic acid (DNA) in the form of neutrophil extracellular traps (NETs). Dornase alfa (Pulmozyme, Genentech) is recombinant human deoxyribonuclease I that acts as a mucolytic by cleaving and degrading extracellular DNA. We performed a pilot study to evaluate the effects of dornase alfa in patients with ARDS secondary to COVID-19.

Methods: We performed a pilot, non-randomized, case-controlled clinical trial of inhaled dornase for patients who developed ARDS secondary to COVID-19 pneumonia.

Results: Improvement in arterial oxygen saturation to inhaled fraction of oxygen ratio (PaO₂/FiO₂₎ was noted in the treatment group compared to control at day 2 (95% CI, 2.96 to 95.66, P-value = 0.038), as well as in static lung compliance at days 3 through 5 (95% CI, 4.8 to 19.1 mL/cmH₂O, 2.7 to 16.5 mL/cmH₂O, and 5.3 to 19.2 mL/cmH₂O, respectively). These effects were not sustained at 14 days. A reduction in bronchoalveolar lavage fluid (BALF) myeloperoxidase-DNA (DNA : MPO) complexes (95% CI, -14.7 to -1.32, P-value = 0.01) was observed after therapy with dornase alfa.

Conclusion: Treatment with dornase alfa was associated with improved oxygenation and decreased DNA : MPO complexes in BALF. The positive effects, however, were limited to the time of drug delivery. These data suggest that degradation of extracellular DNA associated with NETs or other structures by inhaled dornase alfa can be beneficial. We propose a more extensive clinical trial is warranted.

Clinical trial registration: ClinicalTrials.gov, Identifier: NCT04402970.

Keywords: ARDS; COVID - 19; pneumonia; respiratory failure; viral.

Figure 1

Consort flow diagram. A total of 20 patients were evaluated for the study with 8 patients not meeting inclusion criteria and 2 declining to participate. 10 patients were included in the treatment arm with no patients lost to follow up. 20 patients were randomly selected to be a part of the case-control arm (12).

Figure 2

Oxygenation and compliance responses to dornase alfa treatment. (A) Change in PaO₂/FiO₂ compared to day 0. Each colored circle symbol represents a unique patient in the treatment group and each colored triangle symbol represents a unique patient in the control group. A significant increase is noted in the treatment group at day 2 of treatment with a non-statistically significant increase for the additional 14 days. (B) Change in static lung compliance (mL/cmH₂O) compared to day 0. Each colored circle symbol represents a unique patient in the treatment group and each colored triangle symbol represents a unique patient in the control group. Starting on day 3 there was a significant improvement in lung compliance in the treatment group compared to the case control group that was sustained to day 5. No statistically significant difference was noted at 14 days.

Figure 3

Dornase alfa treatment did not reduce BALF neutrophils. Control, day 0 and day 4 symbols are displayed as mean ± SEM of 11 subjects in the control group and 9 subjects in the treatment group. Each individual color-coded point with connecting line between day 0 and 4 represents a unique patient in the treatment group (N=9). Two patients only had samples from a single time point due to sample degradation. Only 11 subjects in the control group underwent BALF sampling during hospitalization and are represented by individual colored coded data points. No statistically significant difference was noted in (A) % Neutrophils, or (B) log transformed absolute neutrophil counts in the bronchoalveolar fluid between case control patients and patients prior to receiving dornase alfa.

Figure 4

Dornase alfa treatment reduced BALF NETs. Symbols on Day 0 and Day 4 are represented as mean ± SEM of 10 subjects in the bronchoalveolar fluid (BALF) analysis and serum neutrophil extracellular traps (NETs) analysis and 9 subjects in the induced NETs analysis. Due to not having the appropriate material prior to sample collection from the first enrolled patient, we were only able to perform induced NET analysis on 9 subjects (C). Each connecting line with points at Day 0 and 4 represents a unique patient sample and is patient colored coded to previous graphs (N=10). NETs defined by NET MPO : DNA complex measurement was significantly reduced in the BALF after 3 days of therapy with dornase alfa (A). There was no significant change in serum NETs or NETs induced in vitro from patient neutrophils harvested after dornase alfa therapy (B, C) respectively.