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0 0.5 1 1.5 2+ Mortality 74% Improvement Relative Risk Ventilation 76% Hospitalization time 20% Budesonide  Gavriilidis et al.  LATE TREATMENT Is late treatment with budesonide + combined treatments beneficial for COVID-19? Retrospective 48 patients in Greece (October 2020 - August 2021) Lower mortality (p=0.045) and ventilation (p=0.023) Gavriilidis et al., Clinical Immunology, Apr 2022 Favors budesonide Favors control

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

Gavriilidis et al., Clinical Immunology, doi:10.1016/j.clim.2022.109016, NCT05279391
Apr 2022  
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Small retrospective study of hospitalized patients with severe respiratory failure, 22 treated with a combination of budesonide, tocilizumab, baricitinib, dornase alfa, and salbutamol or/and ipratropium, and 26 SOC patients, showing lower mortality and intubation with treatment. The average age of the combined treatment group was 6 years younger than the SOC group.
Targeted administration to the respiratory tract provides treatment directly to the typical source of initial SARS-CoV-2 infection and replication, and allows for rapid onset of action, higher local drug concentration, and reduced systemic side effects (early treatment may be more beneficial).
This study is excluded in meta analysis: combined treatments may contribute more to the effect seen.
risk of death, 73.7% lower, RR 0.26, p = 0.045, treatment 2 of 22 (9.1%), control 9 of 26 (34.6%), NNT 3.9.
risk of mechanical ventilation, 76.4% lower, RR 0.24, p = 0.02, treatment 2 of 22 (9.1%), control 10 of 26 (38.5%), NNT 3.4.
hospitalization time, 19.6% lower, relative time 0.80, p = 0.02, treatment mean 15.6 (±5.3) n=22, control mean 19.4 (±7.2) n=26.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Gavriilidis et al., 18 Apr 2022, retrospective, Greece, peer-reviewed, 19 authors, study period 25 October, 2020 - 18 August, 2021, this trial uses multiple treatments in the treatment arm (combined with tocilizumab, baricitinib, dornase alfa, and salbutamol or/and ipratropium) - results of individual treatments may vary, trial NCT05279391 (history).
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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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Late treatment
is less effective
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