Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure
Efstratios Gavriilidis, Christina Antoniadou, Akrivi Chrysanthopoulou, Maria Ntinopoulou, Andreas Smyrlis, Iliana Fotiadou, Nikoleta Zioga, Dionysios Kogias, Anastasia-Maria Natsi, Christos Pelekoudas, Evangelia Satiridou, Stefania-Aspasia Bakola, Charalampos Papagoras, Ioannis Mitroulis, Paschalis Peichamperis, Dimitrios Mikroulis, Vasileios Papadopoulos, Panagiotis Skendros, Konstantinos Ritis
Clinical Immunology, doi:10.1016/j.clim.2022.109016
Aiming to reduce mortality in COVID-19 with severe respiratory failure we administered a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone/heparin) consisted of inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, namely anti-IL-6-receptor tocilizumab and JAK1/2 inhibitor baricitinib. Patients with PaO2/FiO2 < 100 mmHg were analysed. COMBI group (n = 22) was compared with similar groups that had received SOC alone (n = 26) or SOC plus monotherapy with either IL-1-receptor antagonist anakinra (n = 19) or tocilizumab (n = 11). COMBI was significantly associated with lower in-hospital mortality and intubation rate, shorter duration of hospitalization, and prolonged overall survival after a median follow-up of 110 days. In vitro, COVID-19 plasma induced tissue factor/thrombin pathway in primary lung fibroblasts. This effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results support the conduct of randomized trials using combined immunomodulation in COVID-19 to target multiple interconnected pathways of immunothrombosis.
Declaration of Competing Interest None.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.clim.2022.109016.
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