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- Title
Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.
- Authors
Porter, Joanna C; Inshaw, Jamie; Solis, Vincente Joel; Denneny, Emma; Evans, Rebecca; Temkin, Mia I; De Vasconcelos, Nathalia; Aramburu, Iker Valle; Hoving, Dennis; Basire, Donna; Crissell, Tracey; Guinto, Jesusa; Webb, Alison; Esmail, Hanif; Johnston, Victoria; Last, Anna; Rampling, Thomas; Lippert, Lena; Helbig, Elisa Theresa; Kurth, Florian
- 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. 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. 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). Conclusions: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. Funding: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
- Subjects
MEDICAL Research Council (Great Britain); WELLCOME Trust (London, England); COVID-19; LYMPHOCYTE count; MEDICAL research; PNEUMONIA; C-reactive protein; CHROMATIN
- Publication
eLife, 2024, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.87030