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

Holliday et al., Frontiers in Immunology, doi:10.3389/fimmu.2021.714833, NCT04402970, Oct 2021

Non-randomized trial of 10 COVID-19 patients with acute respiratory distress syndrome (ARDS) treated with inhaled dornase alfa, compared to 20 case-control patients, showing improved oxygenation and decreased extracellular DNA-protein complexes in the treatment group. The positive effects were limited to the time of drug delivery and were not sustained at 14 days. The authors propose that degradation of extracellular DNA associated with neutrophil extracellular traps (NETs) by inhaled dornase alfa can be beneficial, and suggest that a more extensive clinical trial is warranted.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments1. Only expensive, high-profit treatments were approved. Low-cost treatments were excluded, reducing the probability of treatment—especially early—due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments. This may explain in part the very high mortality seen in this study. Results may differ in countries with improved SOC.

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risk of death, 11.1% lower, RR 0.89, p = 1.00, treatment 4 of 10 (40.0%), control 9 of 20 (45.0%), NNT 20, day 28.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. c19early.org, c19early.org/soc/usa.html.c19early.org/soc/usa.html.

Holliday et al., 20 Oct 2021, prospective, USA, peer-reviewed, 6 authors, study period 19 June, 2020 - 1 December, 2020, trial NCT04402970 (history). Contact: hollidayz@health.missouri.edu.

This Paper Dornase alfa All

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

Zachary M Holliday, Alexander P Earhart, Mohammed M Alnijoumi, Armin Krvavac, Lee-Ann H. Allen, Adam G Schrum

Frontiers in Immunology, doi:10.3389/fimmu.2021.714833

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 (PaO 2 /FiO 2) 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/cmH 2 O, 2.7 to 16.5 mL/cmH 2 O, and 5.3 to 19.2 mL/cmH 2 O, 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.

ETHICS STATEMENT The studies involving human participants were reviewed and approved by University of Missouri Institutional Review Board. AUTHOR CONTRIBUTIONS ZH, AK, AS, AE, and MA collected and analyzed the data. ZH, AE, and AS wrote the manuscript. AS, AE, AK, L-AA, and MA reviewed/edited the manuscript. All authors contributed to the article and approved the submitted version. Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Copyright © 2021 Holliday, Earhart, Alnijoumi, Krvavac, Allen and Schrum. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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DOI record: { "DOI": "10.3389/fimmu.2021.714833", "ISSN": [ "1664-3224" ], "URL": "http://dx.doi.org/10.3389/fimmu.2021.714833", "abstract": "BackgroundThe 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.MethodsWe performed a pilot, non-randomized, case-controlled clinical trial of inhaled dornase for patients who developed ARDS secondary to COVID-19 pneumonia.ResultsImprovement 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.ConclusionTreatment with dornase alfa was associated with improved oxygenation and decreased DNA : MPO complexes in BALF. 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