Gorman, E. A., O’Kane, C. M. & McAuley, D. F. Acute respiratory distress syndrome in adults: Diagnosis, outcomes, long-term sequelae, and management. Lancet. 400, 1157–1170 (2022).
Meyer, N. J., Gattinoni, L. & Calfee, C. S. Acute respiratory distress syndrome. Lancet. 398, 622–637 (2021).
Azagew, A. W. et al. Global prevalence of COVID-19-induced acute respiratory distress syndrome: Systematic review and meta-analysis. Syst. Rev. 12, 212 (2023).
Parthasarathy, U., Martinelli, R., Vollmann, E. H., Best, K. & Therien, A. G. The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders. Biochem. Pharmacol. 195, 114847 (2022).
Lamers, M. M. & Haagmans, B. L. SARS-CoV-2 pathogenesis. Nat. Rev. Microbiol. 20, 270–284 (2022).
Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).
Retter, A., Singer, M. & Annane, D. The NET effect: Neutrophil extracellular traps—a potential key component of the dysregulated host immune response in sepsis. Crit. Care. 29, 59 (2025).
Paludan, S. R. & Mogensen, T. H. Innate immunological pathways in COVID-19 pathogenesis. Sci. Immunol. 7, eabm5505 (2022).
Veras, F. P. et al. SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology. J. Exp. Med. 217, e20201129 (2020).
Huckriede, J. et al. Evolution of NETosis markers and damps have prognostic value in critically ill COVID-19 patients. Sci. Rep. 11, 15701 (2021).
Middleton, E. A. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood. 136, 1169–1179 (2020).
Shak, S., Capon, D. J., Hellmiss, R., Marsters, S. A. & Baker, C. L. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc. Natl. Acad. Sci. U S A. 87, 9188–9192 (1990).
Jarrahi, A. et al. Recombinant human DNase-I improves acute respiratory distress syndrome via neutrophil extracellular trap degradation. J. Thromb. Haemost. 21, 2473–2484 (2023).
Toma, A., Darwish, C., Taylor, M., Harlacher, J. & Darwish, R. The use of dornase Alfa in the management of COVID-19-Associated adult respiratory distress syndrome. Crit. Care Res. Pract. 2021, 1–6 (2021).
Desilles, J. P. et al. Efficacy and safety of aerosolized intra-tracheal dornase Alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): A structured summary of a study protocol for a randomised controlled trial. Trials 21, 548 (2020).
Alhazzani, W. et al. Surviving sepsis campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Intensive Care Med. 46, 854–887 (2020).
Fuchs, H. J. et al. Effect of aerosolized Recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The pulmozyme study group. N Engl. J. Med. 331, 637–642 (1994).
Scherer, T. et al. A technical feasibility study of dornase Alfa delivery with eFlow® vibrating membrane nebulizers: Aerosol characteristics and physicochemical stability. J. Pharm. Sci. 100, 98–109 (2011).
Sun, S. et al. Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway. Cell. Death Dis. 12, 606 (2021).
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl. J. Med. 370, 2191–2200 (2014).
Taher, A. et al. A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome. Pharmacol. Rep. 73, 1650–1659 (2021).
Zeiher, B. G. et al. Neutrophil elastase Inhibition in acute lung injury: Results of the STRIVE study. Crit. Care Med. 32, 1695–1702 (2004).
Chang, K. H., Moon, S-H., Yoo, S. K., Park, B. J. & Nam, K. C. Aerosol delivery of dornase Alfa generated by jet and mesh nebulizers. Pharmaceutics 12, 721 (2020).
Li, J. et al. Aerosol therapy in adult critically ill patients: A consensus statement regarding aerosol administration strategies during various modes of respiratory support. Ann. Intensive Care. 13, 63 (2023).
Ari, A., Areabi, H. & Fink, J. B. Evaluation of aerosol generator devices at 3 locations in humidified and non-humidified circuits during adult mechanical ventilation. Respir Care. 55, 837–844 (2010).
Hickey, A. J. & Martonen, T. B. Behavior of hygroscopic pharmaceutical aerosols and the influence of hydrophobic additives. Pharm. Res. 10, 1–7 (1993).
Dugernier, J. et al. Inhaled drug delivery: A randomized study in intubated patients with healthy lungs. Ann. Intensive Care. 13, 125 (2023).
Fink, J. B. et al. Reducing Aerosol-Related risk of transmission in the era of COVID-19: An interim guidance endorsed by the international society of aerosols in medicine. J. Aerosol. Med. Pulmonary Drug Deliv. 33, 300–304 (2020).
Rubano, J. A. et al. Tracheobronchial slough, a potential pathology in endotracheal tube obstruction in patients with coronavirus disease 2019 (COVID-19) in the intensive care setting. Ann. Surg. 272, e63–e65 (2020).
Mattson, J. R., Gada, K. D., Jawa, R., Zhang, X. & Ahmad, S. Impact of humidification modality on incidence of endotracheal tube occlusion in COVID-19 patients. J. Intensive Care Med. 39, 965–973 (2024).
Zuo, Y. et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 5, e138999 (2020).
Okur, H. K. et al. Preliminary report of in vitro and in vivo effectiveness of dornase Alfa on SARS-CoV-2 infection. New. Microbes New. Infections. 37, 100756 (2020).
Weber, A. G., Chau, A. S., Egeblad, M., Barnes, B. J. & Janowitz, T. Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: A case series [Internet]. [cited 2025 Mar 24]. Available from: http://medrxiv.org/lookup/doi/. https://doi.org/10.1101/2020.05.13.20087734 (2020).
Porter, J. C. et al. Anti-inflammatory therapy with nebulized dornase Alfa for severe COVID-19 pneumonia: A randomized unblinded trial. eLife. 12, RP87030 (2024).
Holliday, Z. M. et al. Non-Randomized trial of dornase Alfa for acute respiratory distress syndrome secondary to COVID-19. Front. Immunol. 12, 714833 (2021).
Files, D. C. et al. Report of the first seven agents in the I-SPY COVID trial: A phase 2, open label, adaptive platform randomised controlled trial. eClinicalMedicine. 58, 101889 (2023).
Battaglini, D. et al. Challenges in ARDS Definition, Management, and identification of effective personalized therapies. JCM. 12, 1381 (2023).
Ehrmann, S. et al. Inhaled Amikacin to prevent ventilator-associated pneumonia. N Engl. J. Med. 389, 2052–2062 (2023).
Riethmueller, J. et al. Recombinant human deoxyribonuclease shortens ventilation time in Young, mechanically ventilated children. Pediatr. Pulmonol. 41, 61–66 (2006).
Knoch, M. New generation nebulizers. J. Aerosol Med. Pulm Drug Deliv. 37, 157–165 (2024).
Prince, W. S. et al. Pharmacodynamics of recombinant human DNase I in serum. Clin. Exp. Immunol. 113, 289–296 (1998).
Lee, Y. Y. et al. Long-acting nanoparticulate DNase-1 for effective suppression of SARS-CoV-2-mediated neutrophil activities and cytokine storm. Biomaterials 267, 120389 (2021).
Mahri, S. et al. Nebulization of pegylated recombinant human deoxyribonuclease I using vibrating membrane nebulizers: A technical feasibility study. Eur. J. Pharm. Sci. 189, 106522 (2023).
Scozzi, D. et al. Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19. JCI Insight [Internet]. [cited 2025 Jul 4]. Available from: http://insight.jci.org/articles/view/143299 (2021).
Davis, J. C. et al. Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. Lupus. 8, 68–76 (1999).
Gygi, J. P. et al. Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality. J. Clin. Invest. 134, e176640 (2024).
Roe, T. et al. Physiology and pathophysiology of mucus and mucolytic use in critically ill patients. Crit. Care. 29, 68 (2025).
Charbit, A. R. et al. A novel DNase assay reveals low DNase activity in severe asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 326, L796–L804 (2024).
Linssen, R. S. et al. Neutrophil extracellular traps increase airway mucus viscoelasticity and slow mucus particle transit. Am. J. Respir Cell. Mol. Biol. 64, 69–78 (2021).
RECOVERY Collaborative Group et al. Dexamethasone in hospitalized patients with COVID-19. N Engl. J. Med. 384, 693–704 (2021).
Remap-Cap Investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl. J. Med. 384, 1491–1502 (2021).
Bellingan, G. et al. The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: An open-label study. Lancet Respiratory Med. 2, 98–107 (2014).
Kor, D. J. et al. Effect of aspirin on development of ARDS in At-Risk patients presenting to the emergency department: The LIPS-A randomized clinical trial. JAMA. 315, 2406–2414 (2016).
Gál, Z. et al. Plasma neutrophil extracellular trap level is modified by disease severity and inhaled corticosteroids in chronic inflammatory lung diseases. Sci. Rep. 10, 4320 (2020).
McFadyen, J. D., Stevens, H. & Peter, K. The emerging threat of (Micro)Thrombosis in COVID-19 and its therapeutic implications. Circ. Res. 127, 571–587 (2020).
Ranucci, M. et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J. Thromb. Haemost. 18, 1747–1751 (2020).
McElvaney, O. J. et al. A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19. Med 3, 233–248e6 (2022).
Salzmann, M. et al. Neutrophil extracellular traps induce persistent lung tissue damage via thromboinflammation without altering virus resolution in a mouse coronavirus model. J. Thromb. Haemost. 22, 188–198 (2024).
