Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19
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Abstract
Background
Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment.
Methods
We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability postintubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared with tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability of treatment weighting (IPTW).
Results
154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range, 28–67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean: 55 vs 60 years), less likely to have chronic pulmonary disease (10% vs 28%), and had lower D-dimer values at time of intubation (median: 2.4 vs 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR, .55; 95% CI, .33–.90) and improved status on the ordinal outcome scale [OR per 1-level increase, .58; .36–.94). Although tocilizumab was associated with an increased proportion of patients with superinfections (54% vs 26%; P < .001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection (22% vs 15%; P = .42). Staphylococcus aureus accounted for ~50% of bacterial pneumonia.
Conclusions
In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence.
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SciScore for 10.1101/2020.05.29.20117358: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: 17 Ethics approval was obtained by the Institutional Review Board of the University of Michigan. Randomization Patients were excluded if they were younger than 16 years, were intubated for conditions unrelated to COVID-19, or were enrolled into a randomized controlled trial (RCT) for sarilumab. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
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 …SciScore for 10.1101/2020.05.29.20117358: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: 17 Ethics approval was obtained by the Institutional Review Board of the University of Michigan. Randomization Patients were excluded if they were younger than 16 years, were intubated for conditions unrelated to COVID-19, or were enrolled into a randomized controlled trial (RCT) for sarilumab. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
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:However, this analysis is not without limitation. First and foremost, randomized controlled trial data will be critical for confirming the perceived benefits from this observational study and better quantify risks. Second, there were incomplete data for laboratory variables, though we used contemporary methods for imputing missing data. Additionally, we focused on the impact of tocilizumab 8 mg/kg x 1 in mechanically ventilated patients. This study does not address the potential role of tocilizumab earlier in illness for preventing mechanical ventilation, the optimal dose of tocilizumab, the potential utility of multiple doses, or the role of IL-6 serum concentrations (which were not routinely available) in predicting tocilizumab response, all of which are important questions that warrant further investigation. In conclusion, tocilizumab was associated with improved survival, despite higher occurrence of superinfections, in a cohort of COVID-19 patients requiring mechanical ventilation. These data are encouraging and can help to inform clinical practice while results from randomized controlled trials of IL-6 inhibitors are awaited.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04315298 Completed Evaluation of the Efficacy and Safety of Sarilumab in Hospit… 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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