Tocilizumab Effect in COVID-19 Hospitalized Patients: A Systematic Review and Meta-Analysis of Randomized Control Trials

Abstract

Abstract: Since the emergence of the first cases of COVID 19 viral pneumonia late 2019 several studies evaluated the benefits of different treatment modalities. Early in the pandemic, the interleukin 6 (IL 6) receptor antibody Tocilizumab was considered in view of the cytokine release syndrome associated with COVID 19 infection. Several early observational studies showed beneficial effect of treatment with Tocilizumab on mortality, however, results from well designed randomized clinical trials (RCT) were contradicting. Objectives: To perform a systematic literature review and meta-analysis of RCTs utilizing Tocilizumab in the treatment of COVID 19 pneumonia, with in hospital mortality as a primary objective, while secondary objectives included composite outcome of mortality, intubation, or ICU admission, another secondary outcome was super added infection. Method: This was a random effects model (DerSimonian and Laird) model of relative risk (RR), along with corresponding 95% confidence intervals, p values, and forest plots of both primary and secondary outcomes. A fixed effect sensitivity test was performed for the primary outcome, in addition to subgroup and meta regression analyses with predefined criteria. Results: The primary outcome of mortality showed statistically insignificant reduction of mortality with Tocilizumab (RR = 0.9, 95% CI: 0.8 to 1.01; p = 0.09) although with an unmistakable apparent clinical benefit. There was a significant reduction in the RR of the secondary composite outcome (RR = 0.83, 95% CI: 0.76 to 0.9; p < 0.001), and no difference between groups in super added infection (RR = 0.77, 95% CI: 0.51 to 1.19; p = 0.24). Treatment protocol allowing a second dose was the only significant predictor of improved mortality in the meta regression analysis. Certainty of evidence was reduced to moderate for the primary outcome and the secondary outcome of clinical deterioration, while it was reduced to low for the secondary outcome of super added infection. Conclusion: Moderate certainty of evidence suggest no statistically significant improvement of 28-30 day all cause mortality of hospitalized COVID-19 patients treated with TCZ, although there may be clinically important value. Moderate certainty of evidence suggest lowered relative risk of a composite outcome of death or clinical deterioration, while, low grade evidence indicate no increase in the risk of super added infection associated with TCZ treatment. A protocol allowing two doses of TCZ shows evidence of improved mortality as compared to a strictly single dose protocol.