Abstract
To date, there are no specific therapeutic strategies for treatment of COVID-19. Based on the hypothesis that complement and coagulation cascades are activated by viral infection, and might trigger an acute respiratory distress syndrome (ARDS), we report clinical outcomes of 17 consecutive cases of SARS-CoV-2-related ARDS treated (N = 7) with the novel combination of ruxolitinib, a JAK1/2 inhibitor, 10 mg/twice daily for 14 days and eculizumab, an anti-C5a complement monoclonal antibody, 900 mg IV/weekly for a maximum of three weeks, or with the best available therapy (N = 10). Patients treated with the combination showed significant improvements in respiratory symptoms and radiographic pulmonary lesions and decrease in circulating D-dimer levels compared to the best available therapy group. Our results support the use of combined ruxolitinib and eculizumab for treatment of severe SARS-CoV-2-related ARDS by simultaneously turning off abnormal innate and adaptive immune responses.
Highlights
The complement system, a multi-step pathway of the innate immune response, causes pathogen membrane lysis, enhances phagocytosis by macrophages, and releases several pro-inflammatory molecules, such as anaphylatoxins, that amplify inflammation and immune responses. Some of those molecules can trigger the activation of kinin and coagulation cascades which can sustain vascular permeability and thrombosis occurring during acute respiratory distress syndrome (ARDS) (Gralinski et al, 2018; Campbell and Kahwash, 2020; Risitano et al, 2020), and neutrophil and macrophage recruitment at the site of viral infection supporting inflammation and tissue damage
At day 7, patients on ruxolitinib and eculizumab displayed a significant improvement in PaO2 and PaO2/FiO2 ratio compared to the BAT group (P = 0.0260 and P = 0.0395, respectively; unpaired t-test performed) (Figure 1A), while no differences were observed for FiO2 values (P = 0.6630)
No secondary infections were documented in the treated arm (Table 2) suggesting that ruxolitinib 10 mg/twice daily and eculizumab 900 mg IV/ weekly for a maximum of three weeks could be not as immunosuppressive as it might be in a long-period treatment, this combination might be safely used for treatment of SARS-CoV-2-related ARDS
Summary
More than 10% of patients with COVID-19 develop severe respiratory symptoms and an acute respiratory distress syndrome (ARDS) requiring intensive care treatment, and precipitating factors are still under investigation; a massive release of pro-inflammatory cytokines and chemokines from immune cells is one of the main pathogenetic mechanisms (Channappanavar and Perlman, 2017). The complement system, a multi-step pathway of the innate immune response, causes pathogen membrane lysis, enhances phagocytosis by macrophages, and releases several pro-inflammatory molecules, such as anaphylatoxins, that amplify inflammation and immune responses Some of those molecules can trigger the activation of kinin and coagulation cascades which can sustain vascular permeability and thrombosis occurring during ARDS (Gralinski et al, 2018; Campbell and Kahwash, 2020; Risitano et al, 2020), and neutrophil and macrophage recruitment at the site of viral infection supporting inflammation and tissue damage. Based on the hypothesis that SARS-CoV-2 infection triggers a “dog-biting-tail” inflammatory loop, the use of a single anti-inflammatory agent might be not sufficient, a combination of drugs would be advisable in preventing ARDS in intensive care patients (Elli et al, 2019; Sanders et al, 2020) In this controlled study, we reported clinical outcomes of severe COVID-19 treated with the novel combination of ruxolitinib and eculizumab which has never been tested before in any disease. The rationale behind this drug combination is that by acting on different but connected pathways triggered by SARS-CoV-2 infection, we can dramatically turn off inflammation in the lungs reducing the risk of ARDS
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