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

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 (IL-1β), 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.

The role of spike protein entry inhibitors in the treatment of mild-to-moderate covid-19 in nonhospitalized patients

“…48 and GM-CSF. 49 are important targets for blockade in order to ameliorate the immunopathological damage caused by Covid-19, such as acute lung injury, respiratory failure, myocardial injury, and multiorgan damage. There are currently two IL-6 antagonists that have been granted emergency use authorization (EUA) by the US Food and drug Administration (FDA), including tocilizumab.…”

“…58,59 The standard of care (SoC) include high-flow nasal oxygen (HFNO), corticosteroids, remdesivir, and interlekin-6 antagonists, such as tocilizumab, or a Janus kinase inhibitor, including baricitinib. [48][49][50][51][52][53][54][55][56][57][58][59] Critically ill patients with Covid-19 require admission to the intensive care units (ICU), invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). However, ICU admission, and IMV or ECMO are associated with high hospital costs, prolonged multisystem disabilities, such as neurological impairment.…”