eLife (Jul 2024)

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

  • Joanna C Porter,
  • Jamie Inshaw,
  • Vincente Joel Solis,
  • Emma Denneny,
  • Rebecca Evans,
  • Mia I Temkin,
  • Nathalia De Vasconcelos,
  • Iker Valle Aramburu,
  • Dennis Hoving,
  • Donna Basire,
  • Tracey Crissell,
  • Jesusa Guinto,
  • Alison Webb,
  • Hanif Esmail,
  • Victoria Johnston,
  • Anna Last,
  • Thomas Rampling,
  • Lena Lippert,
  • Elisa Theresa Helbig,
  • Florian Kurth,
  • Bryan Williams,
  • Aiden Flynn,
  • Pauline T Lukey,
  • Veronique Birault,
  • Venizelos Papayannopoulos

DOI
https://doi.org/10.7554/eLife.87030
Journal volume & issue
Vol. 12

Abstract

Read online

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). Clinical trial number: NCT04359654.

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