Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients

Pottecher, Julien; Noll, Eric; Borel, M.; Audibert, Gérard; Gette, Sébastien; Meyer, Christian; Gaertner, Élisabeth; Legros, Vincent; Carapito, Raphaël; Uring‐Lambert, B.; Sauleau, Erik; Land, W.; Bahram, Seiamak; Meyer, Alain; M.D., Bernard Geny; Diemunsch, Pierre

doi:10.1186/s13063-020-4141-6

Cited by 14 publications

(11 citation statements)

References 54 publications

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“…The excessive NE activity reported in our study suggests evaluating the use of new generation potent NE inhibitors, including lonodelestat (POL6014), alvelestat, CHF6333, and elafin in COVID‐19 8,27 . The dramatic decrease in DNase reported in our study also suggests evaluating the use of recombinant deoxyribonuclease I (dornase alfa) and/or DNase 1L3 63–65 . One expected effect is the release of NE from degraded NETs, with increased free NE in blood and subsequently improved efficacy of NE inhibitors 30 .…”

Section: Discussionmentioning

confidence: 65%

“…8,27 The dramatic decrease in DNase reported in our study also suggests evaluating the use of recombinant deoxyribonuclease I (dornase alfa) and/or DNase 1L3. [63][64][65] One expected effect is the release of NE from degraded NETs, with increased free NE in blood and subsequently improved efficacy of NE inhibitors. 30 For this reason, we think that the association of DNase inhibitors with NE inhibitors should be considered in the treatment of COVID-19.…”

Section: Discussionmentioning

confidence: 99%

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Elastase and exacerbation of neutrophil innate immunity are involved in multi‐visceral manifestations of COVID‐19

Guéant

Guéant-Rodríguez

Fromonot

et al. 2021

Allergy

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Background Many arguments suggest that neutrophils could play a prominent role in COVID‐19. However, the role of key components of neutrophil innate immunity in severe forms of COVID‐19 has deserved insufficient attention. We aimed to evaluate the involvement of neutrophil elastase, histone‐DNA, and DNases in systemic and multi‐organ manifestations of COVID‐19. Methods We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center, local hospitals, and two regional university hospitals. The cases were evaluated according to clinical and biological markers of severity and multi‐organ manifestations and compared to 35 healthy controls. Results Blood neutrophil elastase, histone‐DNA, myeloperoxidase‐DNA, and free dsDNA were dramatically increased, and DNase activity was decreased by 10‐fold, compared with controls. Neutrophil elastase and histone‐DNA were associated with intensive care admission, body temperature, lung damage, and markers of cardiovascular outcomes, renal failure, and increased interleukin‐6 (IL‐6), IL‐8, and CXCR2. Neutrophil elastase was an independent predictor of the computed tomography score of COVID‐19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL‐8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease in blood DNase activity. Conclusion Our results point out the key role of neutrophil innate immunity exacerbation in COVID‐19. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID‐19.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Elastase and exacerbation of neutrophil innate immunity are involved in multi‐visceral manifestations of COVID‐19

Guéant

Guéant-Rodríguez

Fromonot

et al. 2021

Allergy

View full text Add to dashboard Cite

show abstract

“…The excessive NE activity reported in our study suggests evaluating the use of new generation potent NE inhibitors, including lonodelestat (POL6014), alvelestat, CHF6333, and elafin in COVID-19 8,25 . The dramatic decrease of DNase reported in our study also suggests evaluating the use of recombinant deoxyribonuclease I (dornase alfa) and/or DNase 1L3 [60][61][62] . One expected effect is the release of NE from degraded NETs, with increased free NE in blood and subsequently improved efficacy of NE inhibitors 28 .…”

Section: Discussionmentioning

confidence: 89%

Elastase and Exacerbation of Neutrophil Innate Immunity are Involved in Multi-Visceral Manifestations of COVID-19

Guéant

Gueant

Fromonot

et al. 2020

Preprint

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Background: Many arguments suggest that neutrophils could play a prominent role in COVID-19. However, the role of key components of neutrophil innate immunity in severe forms of COVID-19 has deserved insufficient attention. We aimed to evaluate the involvement of Neutrophil Elastase, histone-DNA, and DNases in systemic and multi-organ manifestations of COVID-19. Methods: We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center (ambulatory subjects), local hospitals, and two regional university hospitals. The case were evaluated according to clinical and biological markers of severity and multi-organ manifestations and compared to 35 healthy controls. Results: Blood Neutrophil Elastase, histone-DNA, myeloperoxidase-DNA and free dsDNA were dramatically increased, and DNase activity decreased by 10-fold, compared to controls. Neutrophil Elastase and histone-DNA were associated with intensive care admission, body temperature, lung damage and markers of cardiovascular outcomes, renal failure and increased IL-6, IL-8 and CXCR2. Neutrophil Elastase was an independent predictor of the computed tomography score of COVID-19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease of blood DNase activity. Conclusion: Our results point out the key role of neutrophil innate immunity exacerbation in COVID-19. Neutrophil Elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID-19.

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“…If NETs play a causal role in the pathogenesis of COVID-19 respiratory failure, aerosolized dornase might bear consideration, 30 as has been reported in other subtypes of ARDS. 31 Bronchodilator use, preferably via in-line metered dose inhalers, could also be considered, especially when significant airflow obstruction interferes with ventilation (for example, when there is evidence of developing auto-PEEP). Recently, a case series showed excellent tolerability of nebulized in-line dornase and albuterol in mechanically ventilated patients with COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Ventilated Patients With COVID-19 Show Airflow Obstruction

Koppurapu

Puliaiev

Doerschug

et al. 2021

J Intensive Care Med

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Objective: Many patients with coronavirus disease 2019 (COVID-19) need mechanical ventilation secondary to acute respiratory distress syndrome. Information on the respiratory system mechanical characteristics of this disease is limited. The aim of this study is to describe the respiratory system mechanical properties of ventilated COVID-19 patients. Design, Setting, and Patients: Patients consecutively admitted to the medical intensive care unit at the University of Iowa Hospitals and Clinics in Iowa City, USA, from April 19 to May 1, 2020, were prospectively studied; final date of follow-up was May 1, 2020. Measurements: At the time of first patient contact, ventilator information was collected including mode, settings, peak airway pressure, plateau pressure, and total positive end expiratory pressure. Indices of airflow resistance and respiratory system compliance were calculated and analyzed. Main Results: The mean age of the patients was 58 years. 6 out of 12 (50%) patients were female. Of the 21 laboratory-confirmed COVID-19 patients on invasive mechanical ventilation, 9 patients who were actively breathing on the ventilator were excluded. All the patients included were on volume-control mode. Mean [±standard deviation] ventilator indices were: resistive pressure 19 [±4] cmH2O, airway resistance 20 [±4] cmH2O/L/s, and respiratory system static compliance 39 [±16] ml/cmH2O. These values are consistent with abnormally elevated resistance to airflow and reduced respiratory system compliance. Analysis of flow waveform graphics revealed a pattern consistent with airflow obstruction in all patients. Conclusions: Severe respiratory failure due to COVID-19 is regularly associated with airflow obstruction.

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Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients

Cited by 14 publications

References 54 publications

Elastase and exacerbation of neutrophil innate immunity are involved in multi‐visceral manifestations of COVID‐19

Elastase and exacerbation of neutrophil innate immunity are involved in multi‐visceral manifestations of COVID‐19

Elastase and Exacerbation of Neutrophil Innate Immunity are Involved in Multi-Visceral Manifestations of COVID-19

Ventilated Patients With COVID-19 Show Airflow Obstruction

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