key: cord-0902898-fmuaoowq authors: Ghazvini, Kiarash; Karbalaei, Mohsen; Keikha, Masoud title: What are the clinical benefits of tocilizumab for COVID-19 patients? Evidence from available case-control studies date: 2020-11-11 journal: nan DOI: 10.1016/j.phclin.2020.11.003 sha: 5879550e8f8280a1067e6cfdb0a429d22edf86e0 doc_id: 902898 cord_uid: fmuaoowq nan In general, individuals infected with SARS-CoV-2 experience different clinical presentations from asymptomatic carrier or initial mild acute respiratory disease, to acute respiratory distress syndrome (ARDS) and organ failure [4, 5] . According to literature, cytokine release syndrome (CRS) plays a central role in immune pathogenesis of SARS-CoV-2 infection and susceptibility to ARDS [6, 7] . Interleukin-6 is responsible for the onset of cytokine storm formation and excessive secretion of inflammatory cytokines [8, 9] . Aziz et al. in their studies revealed increased plasma levels of IL-6 in severe cases of COVID-19 [10] . Based on studies, infected persons to more severe SARS-CoV-2 disease have higher plasma IL-6 levels, and therefore it can be considered as a negative prognostic biomarker for surviving [11] . However, tocilizumab, an anti-human IL-6 receptor, is a humanized monoclonal antibody which targets both membrane and soluble IL-6 receptors [12] . Tocilizumab was approved in 2010 by FDA, and since then widely recommended for rheumatoid arthritis, systemic juvenile idiopathic arthritis, and giant cell arteritis [12, 13] . It seems that the existing anti-IL-6 drug, tocilizumab, has the clinical benefits in reducing the risk of both syndromes CRS and ARDS during the lack of vaccine and appropriate antiviral therapy against SARS-CoV-2 infection. Ramaswamy et al. found that tocilizumab has short-term survival in patients who had got to severe form of COVID-19 [14] . Herein, we conducted a comprehensive statistical analysis on the all available case-control studies which had investigated the therapeutic effects of tocilizumab against COVID-19. In the beginning, we performed a systematic search in several online databases such as PubMed, Scopus, Cochrane Library, Embase, medRxiv, and bioRxiv up to August 2020. Using several keywords according to MeSH such as "SARS-CoV 2", "COVID-19", "2019-nCoV", "tocilizumab", "atlizumab", "actemra", "roactemra", "sarilumab", "kevzara", "siltuximab", and "sylvan", we selected all relevant case-control studies in relation to the efficacy of this anti-IL-6 drug against SARS-CoV-2 cases without language limitation. In the next stage, we started screening the titles and abstracts of identified records, and irrelevant documents were excluded. Subsequently, the full-text of remained literature were evaluated carefully. The Newcastle-Ottawa Scale was used for assessing the quality of included studies. The required data including first author, country, distribution of SARS-CoV-2 infection between the two groups receiving tocilizumab and placebo, tocilizumab dosage, the abundance of death, discharge, requirement for mechanical ventilation, CRP, plasma IL-6 level, patient condition, and Hazard Ratio values for mortality were summarized in the Table I. The primary outcomes including mortality, discharge and requiring mechanical ventilation were measured using the pooled Odds Ratio (OR) with 95% confidence intervals (CIs). In addition, laboratory markers such as CRP and IL-6 were analyzed using the mean (SD) difference with 95% CIs between two groups. Based on DerSimonian-Laird method and using random-effect model, all statistical analyses were performed by Comprehensive Meta-Analysis (CMA) software version 2.2 (Biostat, Englewood, NJ, USA). Heterogeneity was assessed by Cochrane Q test P value ≥ 0.05 and I 2 index > 25%. In addition, publication bias was evaluated by funnel plot, Beggs P value, and Eggers P value [15] . Out of 249 primary identified records, we met only 9 case-control studies, and finally, one of those which had conducted by Wadud According to previous studies, it has been demonstrated that cytokines play a key role in the regulation of immune-system in response to viral infections [24] . Molecular in vitro diagnostic examinations have revealed the expression of interferons (IFNs), IL-1β, IL-6, tumor necrosis factor alpha (TNFα), and chemokines from macrophages infected with SARS-CoV-2. These proinflammatory cytokines can provoke the immune response by constitutive stimulation of immune cells throughout several signaling pathways. Finally, entry of immune cells into the site of infection such as macrophages, neutrophils, and T cells promote apoptosis of pulmonary epithelial / endothelial cells which in turn leads to develop into ARDS [25, 26] . Tocilizumab is an IL-6 antagonist which competitively binds to both soluble and membrane IL-6 receptors, and blocks IL-6 signaling pathways [27] . Therefore, tocilizumab can protect human tissues from destructive effects of cytokine storm via interruption of CRS (Figure 1 ). Liu et al. suggested the blockade of IL-6 for the treatment of severe cases of COVID-19 [28] . In the present quantitative meta-analysis, we also revealed the efficacy of tocilizumab in treating of COVID-19 patients. We found that tocilizumab can significantly reduce mortality rate and [30] . Nevertheless, in rare cases, the usage of tocilizumab can be led to intestinal perforation [31] . Although we observed higher plasma levels of CRP and IL-6 in tocilizumab-treated cases than the control group, but Amoabeng et al. reported a significant decrease of their concentrations following initiation with tocilizumab [32] . The present study has several limitations including: 1) low sample size, 2) low population of studied individuals, 3) different outcomes, 4) diversity of patients' condition in both case and control groups, 5) the presence of heterogeneity between included studies, and 6) publication bias which reduced the reliability of the proposed results. There are 24 registered studies for investigation of clinical benefit of tocilizumab against COVID-19. We showed the efficacy of tocilizumab in reducing mortality rate and requiring mechanical ventilation, but we need to further randomized clinical trials for confirming the present findings. Looming threat of COVID-19 infection in Africa: act collectively, and fast How will country-based mitigation measures influence the course of the COVID-19 epidemic? 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