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Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.
- Source :
-
ELife [Elife] 2024 Jul 16; Vol. 12. Date of Electronic Publication: 2024 Jul 16. - Publication Year :
- 2024
-
Abstract
- Background: 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.<br />Methods: 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.<br />Results: 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).<br />Conclusions: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.<br />Funding: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).<br />Clinical Trial Number: NCT04359654.<br />Competing Interests: JP, VS, ED, RE, MT, ND, IA, DH, DB, TC, JG, AW, HE, VJ, AL, TR, LL, EH, FK, BW, VB, VP No competing interests declared, JI, AF Employee of Exploristics, PL Employee of Target to Treatment Consulting Ltd<br /> (© 2023, Porter et al.)
- Subjects :
- Humans
Male
Female
Middle Aged
Aged
Recombinant Proteins administration & dosage
Recombinant Proteins therapeutic use
Extracellular Traps drug effects
SARS-CoV-2
C-Reactive Protein analysis
C-Reactive Protein metabolism
Dexamethasone administration & dosage
Dexamethasone therapeutic use
Adult
Nebulizers and Vaporizers
Treatment Outcome
Administration, Inhalation
Deoxyribonuclease I administration & dosage
Deoxyribonuclease I therapeutic use
Anti-Inflammatory Agents administration & dosage
Anti-Inflammatory Agents therapeutic use
COVID-19 Drug Treatment
COVID-19
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 39009040
- Full Text :
- https://doi.org/10.7554/eLife.87030