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
Affiliations
Joanna C Porter
UCL Respiratory, University College London, London, United Kingdom; University College London Hospitals NHS Trust, London, United Kingdom
Jamie Inshaw
Exploristics, Belfast, Ireland
Vincente Joel Solis
University College London Hospitals NHS Trust, London, United Kingdom
Emma Denneny
UCL Respiratory, University College London, London, United Kingdom; University College London Hospitals NHS Trust, London, United Kingdom
Rebecca Evans
University College London Hospitals NHS Trust, London, United Kingdom
Mia I Temkin
Antimicrobial Defence Lab, The Francis Crick Institute, London, United Kingdom
Nathalia De Vasconcelos
Antimicrobial Defence Lab, The Francis Crick Institute, London, United Kingdom
Iker Valle Aramburu
Antimicrobial Defence Lab, The Francis Crick Institute, London, United Kingdom
Dennis Hoving
Antimicrobial Defence Lab, The Francis Crick Institute, London, United Kingdom
Donna Basire
UCL Respiratory, University College London, London, United Kingdom
Tracey Crissell
University College London Hospitals NHS Trust, London, United Kingdom
Jesusa Guinto
University College London Hospitals NHS Trust, London, United Kingdom
Alison Webb
University College London Hospitals NHS Trust, London, United Kingdom
Hanif Esmail
University College London Hospitals NHS Trust, London, United Kingdom; National Institute for Health Research, University College London Hospital Biomedical Research Centre, London, United Kingdom
University College London Hospitals NHS Trust, London, United Kingdom; National Institute for Health Research, University College London Hospital Biomedical Research Centre, London, United Kingdom
Anna Last
University College London Hospitals NHS Trust, London, United Kingdom; Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom
Thomas Rampling
University College London Hospitals NHS Trust, London, United Kingdom; National Institute for Health Research, University College London Hospital Biomedical Research Centre, London, United Kingdom
Lena Lippert
Charité – Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany
Elisa Theresa Helbig
Charité – Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany
Florian Kurth
Charité – Universitätsmedizin Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany
Bryan Williams
University College London Hospitals NHS Trust, London, United Kingdom; National Institute for Health Research, University College London Hospital Biomedical Research Centre, London, United Kingdom
Aiden Flynn
Exploristics, Belfast, Ireland
Pauline T Lukey
Target to Treatment Consulting Ltd, Stevenage, United Kingdom
Veronique Birault
Translation, The Francis Crick Institute, London, United Kingdom
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.
