This is a randomized double-blind placebo-controlled Phase II trial of recombinant human deoxyribonuclease I (rhDNase I) - Pulmozyme - in mechanically ventilated patients with COVID-19 pneumonia.

Patients admitted to the ICU with severe COVID-19 pneumonia who require mechanical ventilation will be invited to participate in this study. Potential subjects will be identified from medical record review or from direct contact with physicians. Investigators will check medical history and confirm eligibility. Informed consent will be obtained from either the patient or designated healthcare proxy.

60 subjects will be enrolled. After obtaining informed consent, patients will be randomized 2:1 to Pulmozyme 2.5 mg BID for up to 28 days or until they are no longer receiving mechanical ventilation, whichever is sooner plus standard of care vs. placebo normal saline 2.5 ml plus standard of care.

Inclusion Criteria:

• ICU admission for pneumonia complicated by respiratory failure.
• RT-PCR (or equivalent) confirmed COVID-19 infection.
• Intubated and on mechanical ventilation within 120 hours of initiation of mechanical ventilation.
• Age ≥ 3 years of age.

Exclusion Criteria:

• Allergy or known intolerance to Pulmozyme or Chinese Hamster Ovary cell products
• History of moderate to severe asthma, cystic fibrosis, or severe COPD (baseline FEV1 ≤ 40% predicted)
• Active malignancy other than basal cell melanoma or in situ breast cancer
• Unstable angina
• Chronic liver disease as judged by the investigator that would pose significant risk to participation
• Chronic renal disease as judged by the investigator that would pose significant risk to participation
• Inability to obtain informed consent from patient or legally authorized representative (LAR)
• Pregnant or breastfeeding Use of extracorporeal membrane oxygenation (ECMO)
• Prisoner status
• Concurrent treatment with other inhaled investigational agent for COVID-19**
• Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)
• Moribund patient not expected to survive 24 hours
• Active hemoptysis