Author response: Anti-inflammatory therapy with nebulised dornase alfa for severe COVID-19 pneumonia

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Cell-free (cf)-DNA, from cellular sources, including Neutrophil Extracellular Traps (NETs), is found in the circulation of COVID-19 patients and may contribute to immune dysregulation. This study determined whether pulmonary administration of the endonuclease, dornase alfa, reduced systemic inflammation by degrading local and systemic cf-DNA.Eligible patients were randomized (3:1) to receive twice-daily nebulised dornase alfa in addition to best available care (BAC) or BAC alone for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was improvement in C-reactive protein (CRP) over time, analysed using a repeated-measures mixed model, adjusted for baseline factors.Between June 2020-October 2021 we recruited 39 evaluable patients: 30 randomised to dornase alfa (R-BAC+DA); 9 randomised to BAC (R-BAC); with the addition of 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9mg/L to 23.23 mg/L in the BAC+ dornase alfa group versus a fall from 99.5mg/L to 34.82 mg/L in the T-BAC group at 7 days; P=0.01. This effect of dornase alfa on CRP was confirmed with subgroup and sensitivity analyses that mitigated potential biases associated with the use of the CC-BAC group. Dornase alfa increased the chance of live discharge by 63% (HR 1.63, 95% CI 1.01 to 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).We provide proof-of-concept evidence that dornase alfa reduces pathogenic inflammation in hospitalised patients with COVID-19 pneumonia, suggesting that best available care can be improved by the inclusion of anti-inflammatory treatments that target damage-associated molecules.

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