DISCUSSION
multiorgan dysfunction, death, inflammation, deaths
ADVERSE EVENTS, INFLAMMATION, DISEASE, STRUCK, INFLAMMATORY RESPONSE
Mounting evidence has shown the role of a hyperinflammatory response in the severity of COVID-19, leading to multiorgan dysfunction and death. Targeting inflammatory signaling may be useful for treating COVID-19. Identifying novel treatments for COVID-19 may still have a significant impact on public health, especially in at-risk and socially vulnerable populations without access to vaccination. Herein, as a proof-of-concept, we tested whether the modulation of the inflammatory response via IL-6 (colchicine), IL-17 (ixekizumab), and low doses of IL-2 could improve clinical outcomes of moderate to critical COVID-19 in hospitalized patients. Our findings demonstrate that the use of ixekizumab, colchicine, or low doses of IL-2 is safe, as demonstrated by the low rate of treatment-related adverse events. Interestingly, changes in the cytokine profile were observed with all the treatments, with a decrease in pro-inflammatory cytokines, especially IL-6, and an increase in anti-inflammatory cytokines. Several studies evaluating the cytokine profiles of patients with moderate and severe disease present IL-6 as a predictive biomarker of disease deteriorationColchicine is a promising treatment for patients with moderate-to-critical COVID-19 during their hospital stay. In the colchicine group, all participants showed an improvement of ≥2 points on the WHO 7-point Ordinal Scale (primary endpoint). No deaths or patient deterioration were observed in the colchicine group. We cannot rule out whether the results observed in the colchicine group were favored by randomization issues, which resulted in the allocation of participants with a lower risk of death to this group. Although a possible beneficial effect of colchicine is expected, considering its mechanism of action, conflicting results were found when the drug was used to treat patients with COVID-19. Pascual-Figál (2021), despite not reporting positive effects of colchicine on changes in the WHO 7-point ordinal clinical scale, found that clinical deterioration (+1 WHO scale at any time), need for ICU admission, and progression to mechanical ventilatory support were more frequent in the control groupIn our study, treatment with ixekizumab did not improve patient recovery compared to the SOC. Anti-IL-17 monoclonal antibodies have been previously evaluated in patients with COVID-19. Netakimab treatment in patients with severe COVID-19 decreased inflammation (c-reactive protein (CRP) and IL-6) and significantly improved pulmonary structure and function, leading to reduced ICU requirement and mortality rateA study conducted with patients with severe COVID-19 at the beginning of the pandemic demonstrated the potential of the use of low doses of IL-2 due to its immunomodulatory effect. In the treated group, there was a significant increase in the peripheral lymphocyte count when compared to the non-IL-2 group at discharge. Despite this finding, no differences were observed in the length of hospital stay. Considering that the population covered was very heterogeneous, with a relatively small number of patients tested, further tests are needed to ascertain the effects and safety of this treatmentThe management and drug treatment of patients with COVID-19 who require hospitalization remains challenging. The Solidarity Trial, promoted by the WHO, to treat COVID-19 with antivirals did not have the expected positive impact, driving the international scientific community to seek new treatment alternatives for severely affected patients. Randomization with lopinavir, hydroxychloroquine, and interferon (IFN)-β1a was discontinued for futility; however, the study with remdesivir continued, and the final results showed no significant effect on the in-hospital mortality rate of patients with COVID-19 who were already being ventilated, with only a small effect against death and/or progression to ventilation in other hospitalized patientsOne of the limitations of this study was the small sample size, which might have contributed to the allocation issues. The STRUCK trial was originally conceived as an adaptative study in which a single treatment that has been demonstrated to be more effective in the pilot study (4 arms) would be compared with SOC alone. However, when the pilot study was terminated, the number of hospitalizations in Brazil was dramatically reduced due to vaccination, indicating that a larger trial would not be feasible in a timely manner. Our findings shed light on the potential use of immunomodulators targeting IL-17, 1 L-6, and IL-2 signaling pathways and future trials with larger study populations properly designed to benefit populations with specific characteristics, such as immunocompromised and unvaccinated individuals are needed.