INTRODUCTION
death, tumor necrosis, multiorgan dysfunction, inflammation, hypoxia, autoimmune diseases, infection, deaths, coronavirus disease 2019
DISEASE COMPLICATION, CORONAVIRUS DISEASE 2019, TUMOR NECROSIS, INFLAMMATION, HYPOXIA, DISEASE, AUTOIMMUNE DISEASES, INFECTION, IMMUNOPATHOLOGY, PATHOGENESIS
According to the World Health Organization (WHO), since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there have been approximately 620 million cases worldwide and 6,5 million deaths. Vaccination has significantly decreased the number of cases and hospitalizations, but there are still several barriers to global access to vaccines, which cause vulnerable populations to persist. Uncertainties concerning the duration of vaccine protection and the efficacy against emerging variants raise questions about the risk of infection in already vaccinated individuals. Collectively, these are sufficient reasons to justify the current need for novel treatments. Different therapeutics have been investigated and used to reduce the symptoms and treat COVID-19 including anticoagulants, antiviral drugs, antibiotics, monoclonal antibodies against SARS-CoV-2, systemic corticosteroids, and immunomodulators. The clinical guidelines for COVID-19 management are still being changed and adapted to include new evidenceA complex immune hyperactivation with consequent dysregulation of cytokine release, i.e. the “cytokine storm”, underlies the pathogenesis of COVID-19 and is characterized by systemic inflammation and multiorgan dysfunction. These include elevated blood levels of interleukin-1β (IL-1β), IL-6, tumor necrosis factor (TNF), interferon-γ (IFN-γ), IFN-induced protein 10 (IP-10), macrophage inflammatory protein (MIP) 1α and 1β, and vascular endothelial growth factor (VEGF)IL-6 has been reported as a key contributor to disease complications and is a strong predictor of survival in COVID-19 patientsCrosstalk between IL-17 and IL-6 at the cell signaling level as IL-17 receptor activation increases the expression of IL-6 and can synergize with IL-6 in the induction of pro-inflammatory NF-kB signaling pathwaysOwing to its central role in COVID-19 pathogenesis, IL-6 could be a very attractive target for Covid-19 immunomodulation therapies. The anti-IL-6 receptor monoclonal antibody tocilizumab, investigated in the RECOVERY trial, was shown to reduce 28-day mortality and invasive mechanical ventilation or death when compared to the standard of care (SOC) of hospitalized COVID-19 patients with hypoxia and systemic inflammationCOVID-19 immunopathology and the results from earlier trials continue to make cytokine storm control a promising approach to treating disease; therefore, there is still a need for new evidence aiming to repurpose drugs used for autoimmune diseases as alternative treatments for COVID-19. The present study proposed that modulation of the inflammatory immune response via one of the following targets: IL-6, IL-17, and IL-2 could improve clinical outcomes of COVID-19 patients when compared to the SOC treatment.We aimed to evaluate the efficacy and safety of ixekizumab (IL-17 inhibitor), low-dose IL-2, and colchicine (indirect IL-6 inhibitor) combined with SOC treatment in comparison with SOC alone for the treatment of hospitalized patients with moderate-to-critical COVID-19. 