tetano
Editor, Senior Moderator
Elife
. 2024 Jul 16:12:RP87030.
doi: 10.7554/eLife.87030. Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial
Joanna C Porter[SUP] 1 2 [/SUP], Jamie Inshaw[SUP] 3 [/SUP], Vincente Joel Solis[SUP] 2 [/SUP], Emma Denneny[SUP] 1 2 [/SUP], Rebecca Evans[SUP] 2 [/SUP], Mia I Temkin[SUP] #[/SUP][SUP] 4 [/SUP], Nathalia De Vasconcelos[SUP] #[/SUP][SUP] 4 [/SUP], Iker Valle Aramburu[SUP] #[/SUP][SUP] 4 [/SUP], Dennis Hoving[SUP] #[/SUP][SUP] 4 [/SUP], Donna Basire[SUP] 1 [/SUP], Tracey Crissell[SUP] 2 [/SUP], Jesusa Guinto[SUP] 2 [/SUP], Alison Webb[SUP] 2 [/SUP], Hanif Esmail[SUP] 2 5 [/SUP], Victoria Johnston[SUP] 2 5 [/SUP], Anna Last[SUP] 2 6 [/SUP], Thomas Rampling[SUP] 2 5 [/SUP], Lena Lippert[SUP] 7 [/SUP], Elisa Theresa Helbig[SUP] 7 [/SUP], Florian Kurth[SUP] 7 [/SUP], Bryan Williams[SUP] 2 5 [/SUP], Aiden Flynn[SUP] 3 [/SUP], Pauline T Lukey[SUP] 8 [/SUP], Veronique Birault[SUP] 9 [/SUP], Venizelos Papayannopoulos[SUP] 4 [/SUP]
Affiliations
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).
. 2024 Jul 16:12:RP87030.
doi: 10.7554/eLife.87030. Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial
Joanna C Porter[SUP] 1 2 [/SUP], Jamie Inshaw[SUP] 3 [/SUP], Vincente Joel Solis[SUP] 2 [/SUP], Emma Denneny[SUP] 1 2 [/SUP], Rebecca Evans[SUP] 2 [/SUP], Mia I Temkin[SUP] #[/SUP][SUP] 4 [/SUP], Nathalia De Vasconcelos[SUP] #[/SUP][SUP] 4 [/SUP], Iker Valle Aramburu[SUP] #[/SUP][SUP] 4 [/SUP], Dennis Hoving[SUP] #[/SUP][SUP] 4 [/SUP], Donna Basire[SUP] 1 [/SUP], Tracey Crissell[SUP] 2 [/SUP], Jesusa Guinto[SUP] 2 [/SUP], Alison Webb[SUP] 2 [/SUP], Hanif Esmail[SUP] 2 5 [/SUP], Victoria Johnston[SUP] 2 5 [/SUP], Anna Last[SUP] 2 6 [/SUP], Thomas Rampling[SUP] 2 5 [/SUP], Lena Lippert[SUP] 7 [/SUP], Elisa Theresa Helbig[SUP] 7 [/SUP], Florian Kurth[SUP] 7 [/SUP], Bryan Williams[SUP] 2 5 [/SUP], Aiden Flynn[SUP] 3 [/SUP], Pauline T Lukey[SUP] 8 [/SUP], Veronique Birault[SUP] 9 [/SUP], Venizelos Papayannopoulos[SUP] 4 [/SUP]
Affiliations
- PMID: 39009040
- DOI: 10.7554/eLife.87030
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).