Abstract
Acute respiratory distress syndrome (ARDS), associated with high mortality rate, affects up to 67% of hospitalized COVID-19 patients. Early evidence indicated that the pathogenesis of COVID-19 evoked ARDS is, at least partially, mediated by hyperinflammatory cytokine storm in which interleukin 6 (IL-6) plays an essential role. The corticosteroid dexamethasone is an effective treatment for severe COVID-19 related ARDS. However, trials of other immunomodulatory therapies, including anti-IL6 agents such as tocilizumab and sarilumab, have shown limited evidence of benefit as monotherapy. But recently published large trials have reported added benefit of tocilizumab in combination with dexamethasone in severe COVID-19 related ARDS. In silico tools can be useful to shed light on the mechanisms evoked by SARS-CoV-2 infection and of the potential therapeutic approaches. Therapeutic performance mapping system (TPMS), based on systems biology and artificial intelligence, integrate available biological, pharmacological and medical knowledge to create mathematical models of the disease. This technology was used to identify the pharmacological mechanism of dexamethasone, with or without tocilizumab, in the management of COVID-19 evoked ARDS. The results showed that while dexamethasone would be addressing a wider range of pathological processes with low intensity, tocilizumab might provide a more direct and intense effect upon the cytokine storm. Based on this in silico study, we conclude that the use of tocilizumab alongside dexamethasone is predicted to induce a synergistic effect in dampening inflammation and subsequent pathological processes, supporting the beneficial effect of the combined therapy in critically ill patients. Future research will allow identifying the ideal subpopulation of patients that would benefit better from this combined treatment.