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The role of interleukin-6 and janus kinases in the pathogenesis, and treatment of SARS-CoV-2


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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a deadly pneumonia caused by an enveloped, single-stranded RNA betacoronavirus belonging to the coronaviridae family. Pathophysiologically, SARS-CoV-2 is due to severe hyperinflammatory host response to the coronavirus, resulting in overproduction of cytokines, chemokines, and growth factors by macrophages, such as interleukin-1β (IL1β), IL-2, IL-6, IL-8, IL-10, and tumour necrosis factor-α. SARS-CoV-2 is characterized by diffuse alveolar damage due to direct infection of alveolar type II pneumocytes, pulmonary edema, vascular occlusion, interstitial infiltrates, and ventilation/perfusion mismatch, which rapidly progress to hypoxemia, acute respiratory distress syndrome, multi-organ failure, and death. The standard of care of Covid-19, includes high-flow nasal oxygen (HFNO), dexamethasone, remdesivir, and mechanical ventilation or extracorporeal membrane oxygenation in very severe cases. However, the mortality is exceptionally high even with these therapies. Covid-19 is due to dysregulation, and over-production of cytokines, including IL-1β, IL-6, IL-10, and TNF-α. IL-6 plays a key role in orchestrating the hyperinflammation and the cytokine storm, which leads to acute lung injury, respiratory failure, and multi-organ failure. Interleukin-6 signaling is via the transmembrane IL-6 receptor-α (mIL-6Rα), and the soluble IL-6Rα. Tocilizumab, and sarilumab are IL-6Rα antagonists, and have been issued an emergency use authorization (EUA) by the FDA. Both biologics are safe, and effective in the treatment of severe Covid-19, particularly in patients requiring HFNO, and respiratory support. Another therapeutic approach to treat Covid-19 is to target the downstream JAK/STAT pathway which plays a critical role in inciting IL-6 immunopathological effects. Baricitimab and tofacitinib have been granted EUA by the FDA. A systemic review has shown that JAK-inhibitors significantly decrease odd of mortality (P ? 0.0005), and ICU admission (P ? 0.0005). Additionally JAKinibs significantly increase odds for patient discharge within 2 weeks P ? 0.00001). Tofacitinib has been reported to lead to a lower risk of respiratory failure or death through day 28 than placebo in hospitalized patients with Covid-19. Barictinib in addition to standard of care, including dexamethasone was associated with reduced mortality in hospitalized adults with Covid-19. Selective JAK inhibitors in addition to usual care are effective in the treatment of patients with Covid-19.

Keywords

Covid-19, cytokine storm, interleukin-6, JAK, baricitinib, tofacitinib

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