The role of Janus kinases in the pathogenesis and treatment of covid-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is severe pneumonia caused by an enveloped, single-stranded RNA beta coronavirus, belonging to the coronaviridae family. SARSCoV- 2 is due to severe hyperinflammation in response to the coronavirus 2 infection. This results in overproduction of cytokines, chemokines, and growth factors by macrophages, such as interleukin- 1β (IL-1β), IL-2, IL-6, IL-8, IL-10, and tumour necrosis factor-α, which cause lung and multi-organ damage. Covid-19 pneumonia is characterized by diffuse alveolar damage due to direct infection of alveolar type II pneumocytes, pulmonary enema, interstitial infiltrates, microthrombi, and ventilation/perfusion mismatch. Covid-19 is a progressive disease which ultimately results in acute respiratory distress syndrome, respiratory failure, 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 severe disease. However, the mortality is exceptionally high even with these therapies. IL-6 plays a key role in orchestrating the hyperinflammation and the cytokine storm, which lead to respiratory failure, and multi-organ failure. Interleukin-6 signalling 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 mechanical ventilation. Another therapeutic approach to treat Covid-19 is to target the downstream JAK/STAT pathway which plays a critical role in promoting IL-6, and other cytokines in orchestrating acute respiratory distress syndrome. Baricite and tofacitinib have been granted EUA by the FDA. Both Janus kinase inhibitors have been shown to significantly decrease odds of mortality, and ICU admission. Additionally, JAK inhibitors significantly increase odds for patients’ discharge within 2 weeks. 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. Baricitinib in addition to standard of care, including dexamethasone was associated with reduced mortality in hospitalized adults with Covid-19. Baricitinib is effective in reducing mortality in patients with Covid-19, even in progressive disease stages on mechanical ventilation. Selective JAK inhibitors in addition to usual care are effective in the treatment of hospitalized patients with Covid-19, and in reducing mortality. Keywords: Covid-19; Cytokine storm; Interleukin-6; Janus kinase; JAKinibs; Baricitinib