key: cord-0698675-uyze6dtu
authors: Earhart, Alexander P.; Holliday, Zachary M.; Hofmann, Hunter V.; Schrum, Adam G.
title: Consideration of dornase alfa for the treatment of severe COVID-19 ARDS
date: 2020-04-30
journal: New microbes and new infections
DOI: 10.1016/j.nmni.2020.100689
sha: 2f3f07a33f020f031ea46cf12d45ffc687f410c9
doc_id: 698675
cord_uid: uyze6dtu

nan

where it can lead to mucus plug clearance and accelerated recovery in humans and mice (2, 3) . A controlled clinical trial for treating ARDS with dornase alfa is currently underway (4). In the Critical Care setting, rare and minor adverse effects associated with dornase alfa include voice alteration and rash (1) .

The cellular and molecular mechanism proposed for dornase alfa activity in severely distressed lungs of CF and many ARDS patients is as follows. Inflammation results in neutrophilia and neutrophil infiltration in the lungs, where these cells produce NETs, largely comprised of sticky, large chromosomal DNA that physically reinforces airway mucus viscosity and accumulation (5, 6) . Thick mucus that clears poorly can lead to airway obstruction, bronchiectasis, lung injury, hypoxia, and respiratory failure. Dornase alfa facilitates airway clearance by breaking up reinforcement of mucus by NETs, by far the greatest source of extracellular DNA in inflamed lungs (5, 6) .

neutrophil and mucus-mediated airway exclusion pathway with striking similarities to that described above (Figure 1 ). Unlike mild COVID-19 often associated with fever and upperairway symptoms, patients with severe COVID-19 often progress to an ARDS condition:

hypoxemic respiratory failure associated with neutrophilia and neutrophil infiltration in the lungs, thick mucus in bronchi, and bronchiectasis (7-10). Because lung neutrophilia in ARDS is generally known to involve high NET production (5), we feel it is rational to hypothesize that NETs contribute to severe pathology in COVID-19. Indeed, lung neutrophilia and NET production have been shown to contribute to the development of ARDS in other severe viral respiratory infections, including H1N1 influenza (11) .

We postulate that nebulized dornase alfa may effectively treat a deleterious effect of NETs in the airways and thus promote recovery in patients with COVID-19-related ARDS ( Figure 1 ). Dornase alfa can be easily administered to mechanically ventilated patients and is well tolerated in ICU settings. Anecdotally, a COVID-19 patient who had been intubated five days was given three days of nebulized dornase alfa (2.5mg twice daily) with continued standard ICU care. Improvement in oxygenation and lung compliance were observed comparing before versus after the three-day period (changes: P/F, 212 to 305; Fi0 2 , 65% to 40%; PEEP, 20 to 14).

Four additional days were followed by extubation and six more days in hospital before the patient was considered recovered and discharged home. At this juncture of a rapidly evolving pandemic associated with high mortality in severely ill patients and the concepts discussed above, we suggest consideration to include inhaled dornase alfa in clinical trials for severe COVID-19 associated with ARDS.

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Figure 1. Model of how dornase alfa-sensitive NETs from neutrophils may reinforce mucus accumulation, rigidity, and airway occlusion in severe COVID-19. (A) Viral infection causes 8

Lung-infiltrating neutrophils produce NETs whose large quantities of chromosomal, extracellular DNA are susceptible to degradation by dornase alfa (recombinant human deoxyribonuclease I, right). (B) Close up view of alveoli

Dornase alfa treatment (right) reduces NET-mediated reinforcement of mucus making it less rigid (lighter yellow) and facilitating mucus clearance, thus reducing lung injury and increasing gas exchange. (C) The rate at which recovery from severe COVID-19 occurs naturally (left, thin arrow) might be increased by dornase alfa treatment (right, thicker arrow)