Discussion

To the best of our knowledge, this study is the first meta-analysis built only on the most recent cohort studies to investigate the safety and efficacy of tocilizumab in severe COVID-19. The study searched for the best available evidence evaluating the role of tocilizumab in patients with severe COVID-19 and provided moderate to high quality retrospective cohort studies including 1473 patients in 6 studies. Tocilizumab succeeded in reducing the mortality rate significantly at all-time points; 7, 14, 21, 28 days pooled from all the included studies. Moreover, heterogeneity among the study findings was not significant ensuring that the study findings are consistent. The preventive effect tocilizumab from all-cause mortality was confounded by unequal distribution of some baseline factors, therefore sensitivity analysis was performed after removing the most confounded studies. Repeating the analysis after exclusion of the only two studies with serious risk of confounding bias ensured that the conclusion is robust through finding a little or not at all change in the results after exclusion of the two studies.
Tocilizumab was not superior to the control group regarding improvement in the respiratory supportive level and clinical improvement. This may be due to the low number of patients and studies included in the analysis to estimate pooled RR of either clinical improvement or improvement in the respiratory support level.
In contrast to our results, a recently published meta-analysis that was conducted by Lan et al., (Lan et al., 2020) failed to show significant reduction in all-cause mortality associated with tocilizumab. These results could be explained by the difference in the included studies, where they pooled case-control studies and pre-print studies. Furthermore, the safety of tocilizumab was not investigated.
Regarding the safety of the tocilizumab, the present meta-analysis reported that the incidence of neutropenia and new infections were the only statistically significant parameters in the tocilizumab group. The overall safety outcome favored the control group, although it did not affect the mortality rate because the majority of the reported cases were mild.
Many side effects of tocilizumab have been reported since it has been approved for us in different indications. It includes neutropenia, thrombocytopenia, increased liver enzymes, hypersensitivity, hyperlipidemia, infection, and injection site reactions..etc (Bannwarth & Richez, 2011).
A recent phase 3 clinical trial conducted by Roche was published in August 2020 and provided disappointing results regarding the efficacy of the tocilizumab in the treatment of severe COVID-19 patients (Roche, 2020). This comes congruent with the results provided by our systematic review and metanalysis.
We recommend further randomized clinical trials including larger sample size to be conducted in different stages of the disease, and further studies to clearly identify the exact pathogenesis behind the COVID-19 cytokine storm.
The current evidence of using tocilizumab in severe COVID-19 was based on having a hyper inflammatory conditions (Campochiaro et al., 2020; Ip et al., 2020; Kewan et al., 2020) rather than using H-score to predict cytokines storm which is not validated in COVID-19 patients (Leverenz & Tarrant, 2020). Actually, it was validated to predict hemophagocytic lymphohistiocytosis (HLH) in rheumatic patients (Fardet et al., 2014). Patients’ stratification and well-defined criteria for hyper inflammation-related COVID-19 should be addressed in the future studies to maximize the tocilizumab benefits.