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

Abstract

Background In 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. Methodology PubMed 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). Results Combined 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%. Conclusions Important 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.

Does timing matter on tocilizumab administration? Clinical, analytical and radiological outcomes in COVID-19

“…Other comparable sources reported mortality rates at 30 days in the group treated with tocilizumab of 7.7% in the study by De Rossi et al, 15 16% in the series by Campochiaro et al 16 and 27.7% by Gupta et al 17 The mortality rate reported by Salvarani et al 18 of 3.3% could not be used for comparison because it excluded all patients with criteria for future admission to the ICU. The meta-analysis by Kaye et al 19 reported an overall mortality rate of 16% in 34 studies of the use of tocilizumab. The study by Rojo et al 9 in 6424 Spanish patients reported a mortality rate of 21% in hospitalised patients.…”

The Current Status and Challenges in the Development of Vaccines and Drugs against Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2)

“…COVID-19 patients are characterized by the presence of a dysregulated immune system, hyperinflammation, and very high IL-6 levels. IL-6 is one of the key cytokines implicated in COVID-19 severity and patient mortality [ 102 – 104 ]. Genomic analysis revealed that critically ill patients with COVID-19 exhibit genetic variations in IL-6-mediated inflammatory pathway proteins, which cause life-threatening disease [ 105 ].…”

Mechanisms of Cytokine Storm Development in Covid-19 and New Potential Targets of Pharmacotherapy

“…Опубликованы результаты нескольких метаанализов эффективности тоцилизумаба при COVID-19. Один из недавно опубликованных метаанализов отдельно оценивал результаты контролируемых и неконтролируемых испытаний [56]. Он включал 16 контролируемых исследований с участием в общей сложности 2545 пациентов и показал снижение смертности при терапии тоцилизумабом на 55% в сравнении с контролем (отношение шансов 0,453, 95% доверительный интервал 0,376-0,547, p <0,001).…”

“…Однако данный метаанализ не включал неопубликованные результаты РКИ COVACTA, в котором не было выявлено снижения смертности от COVID-19 при применении тоцилизумаба по сравнению со стандартной терапией, что поставило под сомнение потенциальную эффективность препарата и этическую основу продолжения других исследований [56]. Тем не менее, по-прежнему продолжаются несколько РКИ для оценки эффективности тоцилизумаба у пациентов с новой коронавирусной инфекцией (Идентификаторы ClinicalTrials.gov: NCT04409262, NCT04372186, NCT04356937, NCT04412772).…”