The efficacy of IL-6 inhibitor Tocilizumab in reducing severe COVID-19 mortality: a systematic review.

Avi Gurion Kaye,Robert Siegel

doi:10.7717/peerj.10322

Abstract

BackgroundIn the absence of highly effective antiviral therapies against SARS-CoV-2, it is crucial to counter the known pathophysiological causes of severe COVID-19. Evaluating the efficacy existing drugs may expedite the development of such therapeutics. Severe COVID-19 is largely the result of a dysregulated immune response characterized by lymphocytopenia, neutrophilia and critical hypercytokinemia, or “cytokine storm,” which is largely mediated by the cytokine interleukin-6 (IL-6). The IL-6 inhibitor tocilizumab (TCZ) could potentially suppress the effects of the pro-inflammatory cytokine and thereby lower mortality from the disease. This systematic analysis aimed to investigate and synthesize existing evidence for the efficacy of TCZ in reducing COVID-19 mortality.MethodologyPubMed and SearchWorks searches were performed to locate clinical studies with primary data on TCZ treatment for severe COVID-19. Sixteen case-control studies comparing mortality between TCZ and standard of care (SOC) were identified for quantitative synthesis. The systematic analysis was pre-approved through PROSPERO (CRD42020193479).ResultsCombined mortality for the TCZ-treated and SOC groups were 26.0% and 43.4% respectively. In all but one of the studies, the odds ratio of mortality from COVID-19 pointed towards lower fatality with TCZ vs the SOC. A combined random effects odds ratio calculation yielded an odds ratio of 0.453 (95% CI [0.376–0.547], p < 0.001). Additionally, 18 uncontrolled trials were identified for qualitative analysis producing a raw combined mortality rate of 16.0%.ConclusionsImportant caveats to this research include the lack of prospective randomized control trials and the absence of data from the large COVATA study from the published literature. However, results from this systematic analysis of published research provide positive evidence for the potential efficacy of TCZ to treat severe COVID-19, validating the ethical basis and merit of ongoing randomized controlled clinical trials.

Highlights

Coronavirus Disease 2019 (COVID-19) – caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – manifests in a broad range of disease severity
85% of confirmed cases present as a mild respiratory illness defined as minor fatigue, low-grade fever and dry cough, 15% develop severe pneumonia requiring hospitalization and 5% become critical indicated by acute respiratory distress syndrome (ARDS), septic shock, and multi-organ failure resulting in ICU admission, mechanical ventilation, and death.[1]
A dysregulated immune response – characterized by decreased T-cell counts, increased inflammatory cytokines and extra-pulmonary systemic hyperinflammation syndrome – is principally responsible for inducing critical pulmonary failure observed in COVID-19 and largely driven by interleukin-6 (IL-6).[3]

Summary

Introduction

Coronavirus Disease 2019 (COVID-19) – caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – manifests in a broad range of disease severity. 85% of confirmed cases present as a mild respiratory illness defined as minor fatigue, low-grade fever and dry cough, 15% develop severe pneumonia requiring hospitalization and 5% become critical indicated by acute respiratory distress syndrome (ARDS), septic shock, and multi-organ failure resulting in ICU admission, mechanical ventilation, and death.[1] The most significant known risk factors for COVID-19-related death are increasing age, chronic comorbidities including diabetes, cardiac disease, pulmonary and kidney dysfunction and male sex.[2] A dysregulated immune response – characterized by decreased T-cell counts, increased inflammatory cytokines and extra-pulmonary systemic hyperinflammation syndrome – is principally responsible for inducing critical pulmonary failure observed in COVID-19 and largely driven by interleukin-6 (IL-6).[3] This systematic review concerns the efficacy of an interleukin-6 inhibitor, tocilizumab (TCZ) in reducing severe COVID-19 mortality. COVID-19 Dysregulated Immune Response and the Role of IL-6

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Conclusion