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
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Abstract
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.
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SciScore for 10.1101/2020.11.07.20226837: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The study was approved by the CIMS (Care Institute of Medical Sciences) hospital ethics committee (CTRI/2020/05/025247).
Consent: The need for consent was waived off due to the nature of the study.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data were analyzed using IBM SPSS version 19. SPSSsuggested: (SPSS, RRID:SCR_002865)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected …SciScore for 10.1101/2020.11.07.20226837: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The study was approved by the CIMS (Care Institute of Medical Sciences) hospital ethics committee (CTRI/2020/05/025247).
Consent: The need for consent was waived off due to the nature of the study.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data were analyzed using IBM SPSS version 19. SPSSsuggested: (SPSS, RRID:SCR_002865)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: Our study has many limitations. First, observational studies cannot draw causal inferences because of several confounders, especially absence of a control arm. However, in our viewpoint, a control group would not be rational, considering the role of TCZ in the treatment of CRS, which is a life-threatening condition. Second, misclassifications of data are possible because this was a retrospective cohort study, and data was manually extracted. Third, treatment with TCZ was done at the discretion of treating clinicians, despite a predefined protocol. Fourth, the detailed analysis of timing and doses of steroids is not done in this study, which may be an important factor towards the outcome. Further studies are needed to define the subgroup of patients who would benefit most with the combination of steroids and TCZ, including the optimal timing of administration of both the drugs.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04320615 Completed A Study to Evaluate the Safety and Efficacy of Tocilizumab i… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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