In patients with COVID-19, severe hypoxemic respiratory failure (SRF) leading to invasive mechanical ventilation (IMV), raises the mortality rate substantially. Thus, the management of patients with SRF to avoid intubation and intensive care admission is a challenging and crucial issue.

This study describes, as rescue/compassionate treatment, a therapeutic protocol based on the multi-mechanistic nature of severe COVID-19, using the combination of inhaled DNase, Baricitinib and Tocilizumab on top of standard of care (SOC) consisting of heparin and dexamethasone. COVID-19 patients with SRF who were treated with SOC, SOC plus Anakinra (ANA), and SOC plus Tocilizumab (TOCI) will be studied as comparators. Primary endpoint will be the reduction of the in-hospital mortality rate, whereas secondary endpoints concern intubation rate, days of hospitalization and overall survival as derived from the last follow-up visit, either in-office or remote.

This is a non-randomized, open-label, study, conducted in the First Department of Internal Medicine, University Hospital of Alexandroupolis, Greece.

Inclusion Criteria:

1. adult patients ≥18 years old, of any gender
2. positive polymerase-chain-reaction (PCR) test for SARS-CoV-2 RNA in nasopharyngeal swab
3. pulmonary infiltrates suggestive of COVID-19
4. severe respiratory failure (SRF) as defined by PaO2/FiO2<100 mm Hg
5. written informed consent from the patients or legal representatives for the current compassionate therapeutic protocol.

Exclusion Criteria:

1. need for intubation/IMV during the first 24 hours after the initiation of treatment
2. multi-organ failure,
3. systemic co-infection
4. SRF due to cardiac failure or fluid overload
5. glomerular filtration rate (GFR) <30 ml/min/1.73 m2)
6. any stage IV solid tumor or immunosuppression due to hematological disorders
7. any immunosuppressive therapy and/or chemotherapy during the last 30 days
8. low patient's functional performance as defined by a Palliative Performance Scale (PPS) score ≤30%
9. pregnancy.