Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial

DOI record: { "DOI": "10.7554/elife.87030.4", "ISSN": [ "2050-084X" ], "URL": "http://dx.doi.org/10.7554/eLife.87030.4", "abstract": "<jats:sec id=\"abs1\"><jats:title>Background:</jats:title><jats:p>Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.</jats:p></jats:sec><jats:sec id=\"abs2\"><jats:title>Methods:</jats:title><jats:p>Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.</jats:p></jats:sec><jats:sec id=\"abs3\"><jats:title>Results:</jats:title><jats:p>We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).</jats:p></jats:sec><jats:sec id=\"abs4\"><jats:title>Conclusions:</jats:title><jats:p>Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.</jats:p></jats:sec><jats:sec id=\"abs5\"><jats:title>Funding:</jats:title><jats:p>LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).</jats:p></jats:sec><jats:sec id=\"abs6\"><jats:title>Clinical trial number:</jats:title><jats:p><jats:related-object document-id=\"NCT04359654\" document-id-type=\"clinical-trial-number\" id=\"RO1\" source-id=\"ClinicalTrials.gov\" source-id-type=\"registry-name\" source-type=\"clinical-trials-registry\" 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