This study is designed to evaluate a potential mechanism by which a hyperactive immune response may contribute to death from SARS-CoV-2; by an excessive neutrophil-mediated deposition of cell-free DNA in neutrophil extracellular traps (NET). Excessive amounts of NETs can increase rigidity of mucus, clog airways, and be agents for the development of acute respiratory distress (Narasaraju et al., Am J Pathol. 2011). Many aspects of this pathway have been observed in severe SARS-CoV-2 (Zhang et al., Respiratory research. 2020). Dornase alfa (DNAse I; Pulmozyme (Genentech) is a nebulized drug that works by degrading cell-free DNA and thus promoting airway clearance and recovery. The investigators hypothesize that by thinning mucus and degrading these NETs further lung damage may be prevented and a reduction in time to recovery may occur. The two aims of the study are to see if inhaled/nebulized dornase alfa will improve clinical outcome measures in SARS-CoV-2 related acute respiratory distress syndrome (ARDS) and to see if dornase alfa reduces the amount of bronchoalveolar lavage and blood markers of NET activity. The study will recruit patients who are on mechanical ventilation for respiratory failure related to SARS-CoV-2 positive infection and have ARDS based upon Berlin criteria. The investigators aim to recruit 10-20 patients for this study.
Severe cases of SARS-CoV-2 infection have shown an inflammatory neutrophil and mucus-mediated
airway exclusion pathway similar to previously described acute respiratory distress syndrome
(ARDS) in other viral syndromes (Narasaraju et al., Am J Pathol. 2011). Lung neutrophilia in
ARDS is related to significant neutrophil extracellular trap (NET) production and formation.
Thus, NET production is likely contributing to the severe lung pathology in SARS-CoV-2 (Yu
Zuo et al. Journal of Clinical Investigation Insight. 2020). Recent connections have been
made between NET formation in SARS-CoV-2 patients and excessive thrombosis and the
development of cytokine storm further warranting evaluation as a potential site for
consideration of treatment (Barnes, Betsy et al. J exp Med. 2020). Dornase alfa (Pulmozyme)
is a recombinant human deoxyribonuclease I, that acts as a mucolytic by cleaving
extracellular chromosomal DNA from NETs and other cell-free DNA. Unknown are the effects of
dornase alfa therapy on SARS-CoV-2 related ARDS and if therapy with dornase alfa truly
reduces the amount of NETs in the severely damaged lungs.
This study is a non-randomized, single-center, open-label clinical trial to evaluate the
potential benefit and cellular mechanism of nebulized dornase alfa administration in
mechanically ventilated patients with SARS-CoV-2 related ARDS. Evaluation of dornase alfa
effects at a cellular level will be measured by analysis of blood samples before and after
the 3 days of therapy for cell-free DNA, quantification of citrullinated histone H3,
quantification of Myeloperoxidase-DNA complexes and analysis of bronchoalveolar lavage
samples for quantification of NETs and cell count and differential.
Drug: Dornase Alfa Inhalation Solution
Nebulized dornase alfa
Other Name: Pulmozyme
Inclusion Criteria:
- Age > 18 years
- Hospitalized and mechanically ventilated for illness related to SARS-CoV-2
- Confirmed positive SARS-CoV-2 infection by Polymerase chain reaction (PCR)
- individual or surrogate ability to sign informed consent
- negative, urine-based pregnancy test in females
Exclusion Criteria:
- contraindication or intolerance to dornase alfa
- mechanical ventilation expected to be less than 48 hours
- life expectancy less than 24 hours based upon judgement of treating physician
- pregnant
- inability to obtain informed consent
University of Missouri Hospital and Clinics
Columbia, Missouri, United States