Evaluating the Efficacy of Tocilizumab in Moderate to Severe COVID-19 with Progressive Illness despite Steroids: Identifying the Optimal Timing of its Administration in C3G study

Madan, S.; Rana, M.; Gajjar, R.; Shah, N.; Thakkar, V.; Shah, B.; Dabhi, P.; Patel, M.; Shah, H.; Chovatiya, R.; Soni, M.; Bapat, N.; Patel, A.

Background High mortality has been described in coronavirus disease 2019 (COVID-19) with cytokine release syndrome (CRS). Tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist may be associated with improved outcomes in such patients; however, the subgroups of patients who benefit the most need to be identified. Objective To analyze the efficacy and optimal timing of administration of TCZ in moderate to severe COVID-19 with features of CRS, where the response to steroids was poor. Methods This is a retrospective study of 125 patients admitted between May 5 to July 31, 2020, in a tertiary care hospital in western India, with moderate to severe COVID-19 who were treated with TCZ along with steroids. The primary outcomes were the need for mechanical ventilation (MV) or death, and secondary outcomes were a decrease in oxygen requirement and inflammatory markers; the incidence of secondary infections, and renal or hepatic dysfunction. Kaplan Meier survival analysis and log rank test were used for evaluating primary outcomes. Secondary outcomes were analyzed using the Wilcoxon Signed-Rank test. Results Among 1081 patients admitted during the study period, 125 were administered TCZ (median age, 56 [95% CI 54 - 60] years; 100 [80%] male). The commonest symptoms were fever (96%), cough (64%), and dyspnea (48.8%). 78.4% patients had comorbidities (hypertension 51.2%, diabetes 43.2%, obesity 25.6% and chronic cardiac disease 13.6%). Of 117 patients who were treated with TCZ before requiring MV, 18.8% progressed to MV. Overall, 25% of the patients needed MV support. 65.3% of patients were discharged by day 14 after TCZ administration. Mortality was nil, 16.2%, 50%, and 62.5% in patients who received TCZ on room air, low flow oxygen, high flow nasal cannula (HFNC) and bilevel positive airway pressure (BiPAP), and MV respectively; overall 24.8% of patients died. Survival analysis showed no difference in outcome with respect to age and gender, while progression to MV showed a statistically significant reduction for the event death (90.9% of patients who progressed to MV died as compared to 6.3% who did not; log rank test with p < 0.0001). No adverse events were noticed. Conclusion Mortality was least in patients of COVID-19 with CRS who received TCZ while on low flow oxygen. When administered in the early hypoxemic phase, TCZ is associated with reduced mortality and decreased need for mechanical ventilation.