Tocilizumab and COVID-19: Timing of Administration and Efficacy

Abstract

Elevated concentrations of interleukin-6 have been demonstrated to be an important key factor in COVID-19 host immune impairment. It represents an important prognostic factor of harm associated with COVID-19 infection by stimulating a vigorous proinflammatory response, leading to the so-called "cytokine storm". Therefore, immunomodulatory interventions targeting interleukin-6 receptor antagonism have been investigated as potential treatments to counterbalance the host immune dysregulation and to support the advantageous effects of corticosteroids. Tocilizumab is a recombinant humanized monoclonal antibody that has gained much interest during the COVID-19 pandemic as an interleukin-6 receptor antagonist. Various early observational studies have reported beneficial effects of tocilizumab. Moreover, consequent randomized controlled trials have subsequently shown significant positive results about tocilizumab efficacy and safety, focusing on outcomes like mortality, risk of intensive care unit admission, and the need for mechanical ventilation, while others presented conflicting findings. In this review, we first described the pathophysiology of COVID-19 infection while highlighting the role of interleukin-6. Furthermore, we also discussed the non-conclusive evidence about tocilizumab to be used as the standard of care therapy for all patients with COVID-19 pneumonia, as well as its beneficial effects in selected patients.

Keywords: COVID-19 infection; SARS-CoV-2 infection; acute respiratory distress syndrome; cytokine storm; intensive care unit; interleukine -6 receptor antagonist; invasive mechanical ventilation; tocilizumab.

FIGURE 1

Schematic Representation of Physiological Host Response to SARS-CoV-2 Infection with A and B representing the disease severity and related events: A: Viral entry and early infection (Proptosis induction): (World Health Organization, 2020): SARS-CoV-2 viral infection of alveolar epithelial cells via surface binding of spike (S) protein to angiotensin converting enzyme 2 facilitated by transmembrane serine protease 2: SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; TMPRSS2: S protein priming; ACE-2: Angiotensin-Converting Enzyme 2; AngII-AT1R: AngII-angiotensin type 1 receptor; VRNA: Viral Ribonucleic Acid; R: Ribosome; 1: Fusion; 2: Translation; 3: Proteolysis; 4: Translation and RNA replication; 5: Packaging; 6: Virion release.

FIGURE 2

Host immune response: pulmonary recruitment of macrophages and dendritic cells in response to chemokine and cytokine release: Characterised by DAMP/PAMPs recognition, pro-inflammatory cytokine and chemokine release (early phase), activation of different cells of the mononuclear phagocyte system and virus specific cytotoxic T cells recruitment (late phase). Activated macrophages, monocytes and dendritic cells secrete IL-6 in increased quantities: IFN-γ: Interferon-γ; TNF-α: Tumor necrosis factor-α; ARDS: Acute Respiratory Distress Syndrome; PO2: Partial Pressure of Oxygen; SNS: Somatic Nervous System; HR: Heart Rate; RR: Respiratory Rate; IL: Interleukin; CRS: Cytokine Release Syndrome. : Alveoli Cross section; : Viral proteins; : Polypeptide chain; : Respiratory Epithelial cell; : Activated Neutrophil; : Migrating Neutrophil; : Activated Macrophage; : Activated Monocyte; : Activated Dendritic cell; : Fibroblast; : Platelets.

FIGURE 3

Schematic Representation of Pathogenic Host Response to SARS-CoV-2 and Pathways to Cytokine Release Syndrome (CRS): (A): Hyperinflammatory phase: CRS characterised by excessive concentrations of IL-6 leading to an amplified IL-6–sIL-6R–JAK-STAT3 Cis and Trans signaling pathways with, respectively, lymphocyte and vascular changes in multiple cell types such as lymphocytes and endothelial cells characterised by excessive infiltration of immune cells in the lungs, systemic overproduction of pro-inflammatory cytokines and aberrant regulation. (B): Multiorgan dysfunction: Characterised by extrapulmonary organs involvement, sHLH, ARDS and ultimately to COVID-19 patients’ death. Immunomodulatory treatment by IL-6 antagonists is represented by TCZ directed against both the soluble and the membrane-bound forms of IL-6R to inhibit both CIS and Trans singling pathways: Glycoprotein 130: gp 130; mIL-6R: membrane-bound IL-6 receptor; sIL-6R: soluble IL-6 receptor; JAK: Janus kinase; MCP-1: Monocyte Chemoattractant Protein–1; STAT3: Signal Transducer and Activator of Transcription 3; T _FH : T follicular helper cell; T _H17 : T helper 17 cell; TPO: Thrombopoietin; T _reg : T regulatory cell; VEGF: Vascular Endothelial Growth Factor; C3: Complement 3; CRP: C Reactive Protein; TCZ: Tocilizumab; : Endothelial cell; : Lymphocyte.