Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality

Abstract

Since December 2019, a viral pneumonia, named coronavirus disease 2019 (COVID-19), from Wuhan, China, has swept the world. Although the case fatality rate is not high, the number of people infected is large and there is still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is an important cause of death. Therefore, treatment of the cytokine storm has become an important part of rescuing severe COVID-19 patients. Interleukin-6 (IL-6) plays an important role in cytokine release syndrome. If it is possible to block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe COVID-19 patients. Tocilizumab is an IL-6 receptor (IL-6R) blocker that can effectively block the IL-6 signal transduction pathway and thus is likely to become an effective drug for patients with severe COVID-19.

Keywords: COVID-19; Cytokine release syndrome; IL-6; IL-6R; Tocilizumab.

Fig. 1

Possible mechanism of cytokine release syndrome in severe coronavirus disease 2019 (COVID-19) patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects alveolar epithelial cells [mainly alveolar epithelial type 2 (AEC2) cells] through the angiotensin-converting enzyme 2 (ACE2) receptor. Destruction of epithelial cells and the increase of cell permeability lead to release of the virus. SARS-CoV-2 activates the innate immune system; macrophages and other innate immune cells not only capture the virus but also release a large number of cytokines and chemokines, including interleukin-6 (IL-6). Adaptive immunity is also activated by antigen-presenting cells (mainly dendritic cells). T- and B-cells not only play an antiviral role but also directly or indirectly promote the secretion of inflammatory cytokines. In addition, under the stimulation of inflammatory factors, a large number of inflammatory exudates and erythrocytes enter the alveoli, resulting in dyspnoea and respiratory failure.

Fig. 2

Brief introduction to interleukin-6 (IL-6). CTL, cytotoxic T lymphocyte; CRS, cytokine release syndrome; COPD, chronic obstructive pulmonary disease; gp130, glycoprotein 130; IL-6R, interleukin-6 receptor.

Fig. 3

Signal transduction pathways of interleukin-6 (IL-6): (A) classical signal transduction; (B) trans signal transduction; and (C) trans-presentation. (D) The next step is to activate the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway (STAT1, STAT3 and, to a lesser extent, STAT5); in addition, the RAS-RAF, SRC-YAP-NOTCH and AKT-PI3K pathways are also activated. These promote complex biological functions such as proliferation, differentiation, oxidative stress and immune regulation, etc. IL-6R, interleukin-6 receptor; gp130, glycoprotein 130; sIL-6R, soluble interleukin-6 receptor; sgp130, soluble glycoprotein 130;