Use of Tocilizumab in COVID-19: A Systematic Review and Meta-Analysis of Current Evidence

Abstract

Background and objectives A flare-up in coronavirus disease 2019 (COVID-19) cases threatens the health of people, and though there is no proven pharmacological treatment, many analytical studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of severe COVID-19 and that the anti-IL-6 biologic agent tocilizumab may be beneficial. This is a critical review of studies aiming to assess the safety and efficacy of tocilizumab as compared to the standard regimen in patients with COVID-19. Materials and methods Online databases (PubMed and Cochrane) were searched until June 29, 2020, for original articles investigating the immunological response in COVID-19 and its treatment with tocilizumab. Data on multiple baseline characteristics and pre-specified endpoints were extracted and pooled using a random effect model. We used Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Denmark) and Stata 11.0 (Stata Corporation LP, College Station, TX) for all analyses. Risk ratios (RR) and the weighted mean difference (WMD) with the corresponding 95% confidence interval (CI) were calculated. Results From a total of 1,246 identified articles, 13 studies were included after duplicate removal and narrowing based on title and abstract. Of the 13 included studies, seven case-control studies were shortlisted for metaanalysis (quantitative) and six-single arm studies were used in the discussion (qualitative). These studies had 766 patients (351 in the tocilizumab arm and 414 in the control arm). Their pooled analysis demonstrated that mortality was significantly lower in the tocilizumab group (RR=0.56 [0.34, 0.92]; p=0.02; I 2 =76%), as was the need for artificial invasive ventilation (RR=0.34 [0.12, 0.99]; p=0.05; I 2 =0%) as compared to the control group. No significant differences were observed between tocilizumab and control group in intensive care unit admissions (RR=0.73 [0.15, 3.59]; p=0.70; I 2 =60%) and risks of post-drug infection (RR=1.29 [0.41, 4.04]; p=0.66; I 2 =88%). In terms of efficacy outcome, improved oxygen saturation (RR=1.13 [1.04, 1.65]; p=0.02; I 2 =0%) was reported to be markedly significant in tocilizumab patients when compared with the standard care group. Conclusions Our results based on pooled studies show tocilizumab to be safe and efficacious in reducing mortality among critically ill COVID-19 patients. However, due to the limited number of observational studies, the positive findings should be viewed cautiously and warrant further investigation.

Efficacy and safety of Tocilizumab in severe and critical COVID-19: A Systematic Review and Meta-Analysis

“…Similar results were obtained by previous meta-analysis studies on the effect of tocilizumab treatment on the mortality risk of COVID-19 patients. Khan et al [ 87 ], Rubio-Rivas et al [ 88 ], and Kotak et al [ 89 ] reported RRs [95%CIs] of 0.83 [0.72, 0.96], 0.73 [0.57, 0.93], and 0.56 [0.34, 0.92], respectively, and Zhao et al [ 90 ] and Sarfraz et al [ 91 ] reported odds ratios [95%CIs] of 0.44 [0.36, 0.55] and 0.42 [0.26, 0.69], respectively, with tocilizumab treatment compared with SOC. Despite the promising results in these meta-analysis studies, none of the four published RCTs found a significant beneficial effect on mortality rates for tocilizumab in COVID-19 patients.…”

“…Tleyjeh et al [ 92 ] in the meta-analysis of four RCTs reported a pooled RR [95%CI] of 0.71 [0.52, 0.96] for the effect of tocilizumab on mechanical ventilation. Similarly, Kotak et al [ 89 ] demonstrated a lower risk of the need for intubation with a RR [95%CI] of 0.34 [0.12, 0.99]; and Aziz et al [ 93 ] reported lower rates of mechanical ventilation with a risk difference [95%CI] of −0.11 [−0.19, −0.02] in tocilizumab patients. In a recent retrospective study, Salvati et al [ 94 ] found improved alveolar-arterial oxygen gradient and pulmonary vascular radiologic score in severe COVID-19 patients 1 week after tocilizumab treatment.…”

“…Regarding safety, almost all published meta-analysis studies reported no significant differences in the rate of clinically important infections between the tocilizumab and SOC groups [ 89 , 92 , 95 , 96 ]. Similarly, in our study, no significant association between tocilizumab administration and secondary infections was found (RR [95%CI] of 1.24 [0.98, 1.56]).…”

Revised Korean Society of Infectious Diseases/National Evidence-based Healthcarea Collaborating Agency Guidelines on the Treatment of Patients with COVID-19

“…In six recently published systematic reviews and meta-analyses, the effects of tocilizumab on mortality in patients with severe COVID-19 were not consistent. In four studies, tocilizumab treatment significantly reduced the mortality rate [ 155 156 157 158 ], while opposite findings were observed in two other studies [ 159 160 ].…”

A proposed insight into the anti-viral potential of metallic nanoparticles against novel coronavirus disease-19 (COVID-19)

“…There were no TCZ -linked complications or illness deterioration (Zhanga et al 2020) TCZ increases the risk of cardiovascular disease (Zhanga et al 2020) TCZ might cause some adverse effects including hepatic damage, neutropenia, thrombocytopenia, or serious secondary infection (Zhangb et al 2020;Kotak et al 2020) Remdesivir (RDV) (A prodrug of an adenosine analogue) RDV is a broad-spectrum antiviral agent and a potent inhibitor of SARS-CoV-2 replication in nasal and bronchial airway epithelial cells (Doggrell 2020) RDV decreases the recovery-time in COVID-19 patients and currently is the first approved anti-viral drug against COVID-19 (Beigel et al 2020) RDV might cause some side effects such as the elevation in hepatic enzyme levels and diarrhea (Grein et al 2020) The poor oral-bioavailability of RDV hindered its prophylactic use (Malin et al 2020) Lopinavir/ritonavir (LPVr) (a protease inhibitor) LPV/r plays an important role in the "early stage i.e. initial 7-10 days" clinical outcome (Yao et al 2020 re-emergence of viral outbreaks, knowing that the vaccines require pre-clinical trials and about 10 months for approval and commercialization.…”