RESUMO
COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppress macrophage anti-inflammation and efficient tissue repair programs and provide mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.
RESUMO
IntroductionNeutrophilia and high levels of proinflammatory cytokines and other mediators of inflammation are common finds in patients with severe acute respiratory syndrome due to COVID-19. By its action on leukocytes, we propose colchicine as an intervention worthy of being tested. ObjectiveTo evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes. MethodsWe present the interim analysis of a single-center randomized, double-blinded, placebo controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 38 patients allocated 1:1 from April 11 to July 06, 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The first dose was 1.0 mg whether body weight was [≥] 80 kg. EndpointsThe primary endpoints were the need for supplemental oxygen; time of hospitalization; need for admission and length of stay in intensive care units; and death rate and causes of mortality. As secondary endpoints, we assessed: serum C-reactive protein, serum Lactate dehydrogenase and relation neutrophil to lymphocyte of peripheral blood samples from day zero to day 7; the number, type, and severity of adverse events; frequency of interruption of the study protocol due to adverse events; and frequency of QT interval above 450 ms. ResultsThirty-five patients (18 for Placebo and 17 for Colchicine) completed the study. Both groups were comparable in terms of demographic, clinical and laboratory data at baseline. Median (and interquartile range) time of need for supplemental oxygen was 3.0 (1.5-6.5) days for the Colchicine group and 7.0 (3.0-8.5) days for Placebo group (p = 0.02). Median (IQR) time of hospitalization was 6.0 (4.0-8.5) days for the Colchicine group and 8.5 (5.5-11.0) days for Placebo group (p = 0.03). At day 2, 53% vs 83% of patients maintained the need for supplemental oxygen, while at day 7 the values were 6% vs 39%, in the Colchicine and Placebo groups, respectively (log rank; p = 0.01). Hospitalization was maintained for 53% vs 78% of patients at day 5 and 6% vs 17% at day 10, for the Colchicine and Placebo groups, respectively (log rank; p = 0.01). One patient per group needed admission to ICU. No recruited patient died. At day 4, patients of Colchicine group presented significant reduction of serum C-reactive protein compared to baseline (p < 0.001). The majority of adverse events were mild and did not lead to patient withdrawal. Diarrhea was more frequent in the Colchicine group (p = 0.17). Cardiac adverse events were absent. DiscussionThe use of colchicine reduced the length of supplemental oxygen therapy and the length of hospitalization. Clinical improvement was in parallel with a reduction on serum levels of C-reactive protein. The drug was safe and well tolerated. Colchicine may be considered a beneficial and not expensive option for COVID-19 treatment. Clinical trials with larger numbers of patients should be conducted to further evaluate the efficacy and safety of colchicine as an adjunctive therapy for hospitalized patients with moderate to severe COVID-19.
