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

• Published in: eLife 2024-07, Vol.12
• Main 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, Williams, Bryan, Flynn, Aiden, Lukey, Pauline T, Birault, Veronique, Papayannopoulos, Venizelos
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Adult; Aged; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - therapeutic use; Bacterial artificial chromosomes; Body mass index; C-reactive protein; C-Reactive Protein - analysis; C-Reactive Protein - metabolism; Chemical compounds; Chromatin; Consent; Coronaviruses; COVID-19; COVID-19 Drug Treatment; Cystic fibrosis; Deoxyribonuclease I - administration & dosage; Deoxyribonuclease I - therapeutic use; Dexamethasone; Dexamethasone - administration & dosage; Dexamethasone - therapeutic use; DNA; DNase; dornase alfa; Endonuclease; Extracellular Traps - drug effects; Female; Females; histone; Hospitalization; Humans; Immunology and Inflammation; Inflammation; Leukocytes (neutrophilic); Lymphocytes; Male; Medical prognosis; Medical research; Medicine; Middle Aged; Nebulizers and Vaporizers; NETs; Neutrophils; Oxygen saturation; Patients; Pneumonia; Reagents; Recombinant Proteins - administration & dosage; Recombinant Proteins - therapeutic use; SARS-CoV-2; Sensitivity analysis; Treatment Outcome; Viral infections
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.87030

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. 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. 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). Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). NCT04359654.