Disarming exorbitant neutrophil responses using aerosolized Dnase I/Pulmozyme in COVID-19 associated acute respiratory distress syndrome; a phase-II trial.

Background:

COVID-19 results in acute respiratory distress syndrome (ARDS) and can be fatal. The role of neutrophils, the most important innate immune cell type in exacerbations during COVID-19 is relatively unknown. During viral infections, neutrophils extrude a network of DNA and inflammatory proteins called neutrophil extracellular traps (NETs) that can cause mucus thickening, coagulation and inflammation in airways.

The role of NETs in driving lung inflammation and respiratory failure in COVID-19 remains undescribed. Findings:

We identified NETs in sputum in COVID patients using advanced microscopy and proteomics. NETs could be rapidly degraded with the DNase I treatment, a clinically registered drug used in cystic fibrosis treatment (Pulmozyme). Treatment quickly reduced the need for oxygen and intensive care in critically ill COVID patients.

Based on this, we will conduct a phase-II randomized study to investigate if DNase I is effective in severe COVID-19 disease with respiratory failure and if treatment neutralizes severe inflammation and coagulation. Method:

A randomized phase-II clinical trial to study benefits of aerosolized Pulmozyme and 0.9% NaCl as placebo will be conducted in Lund University hospital and Helsingborg University hospital. Patients will be treated for 5 days and monitored for clinical efficacy for 28 days. Sputum Samples will be analyzed using immunofluorescence microscopy and cutting-edge proteomics to determine treatment efficacy and monitor treatment, and also delineate mechanisms that drive NET formation.

Conclusions:

NETs contribute to COVID-19 etiology by causing severe pulmonary inflammation and respiratory failure. Our preliminary data suggests that Pulmozyme rapidly dissolves NETs and reduces oxygen demand and lung damage. Respiratory failure in severe COVID-19 has led to a great need for respirators globally.

Thus, it is crucial to explore new therapeutic alternatives that reduce requirement of respiratory care. In this research proposal, we illustrate a strategy where early intervention inhibits inflammation and reverses hypoxia. This reduces the need for advanced respiratory care for critically ill COVID patients.

Also, we could monitor changes in thousands of proteins accompanying recovery with treatment using mass spectrometry. Our studies will help enable the discovery of new biomarkers for the prediction and monitoring of treatment efficacy, and develop new therapies for the treatment of COVID-19.