The efficacy of IL-6 inhibitor Tocilizumab in reducing severe COVID-19 mortality: a systematic review
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Abstract
In the absence of highly effective antiviral therapies against SARS-CoV-2, it is crucial to counter the known pathophysiological causes of severe COVID-19. Evaluating the efficacy existing drugs may expedite the development of such therapeutics. Severe COVID-19 is largely the result of a dysregulated immune response characterized by lymphocytopenia, neutrophilia and critical hypercytokinemia, or “cytokine storm,” which is largely mediated by the cytokine interleukin-6 (IL-6). The IL-6 inhibitor tocilizumab (TCZ) could potentially suppress the effects of the pro-inflammatory cytokine and thereby lower mortality from the disease. This systematic analysis aimed to investigate and synthesize existing evidence for the efficacy of TCZ in reducing COVID-19 mortality.
Methodology
PubMed and SearchWorks searches were performed to locate clinical studies with primary data on TCZ treatment for severe COVID-19. Sixteen case-control studies comparing mortality between TCZ and standard of care (SOC) were identified for quantitative synthesis. The systematic analysis was pre-approved through PROSPERO (CRD42020193479).
Results
Combined mortality for the TCZ-treated and SOC groups were 26.0% and 43.4% respectively. In all but one of the studies, the odds ratio of mortality from COVID-19 pointed towards lower fatality with TCZ vs the SOC. A combined random effects odds ratio calculation yielded an odds ratio of 0.453 (95% CI [0.376–0.547], p < 0.001). Additionally, 18 uncontrolled trials were identified for qualitative analysis producing a raw combined mortality rate of 16.0%.
Conclusions
Important caveats to this research include the lack of prospective randomized control trials and the absence of data from the large COVATA study from the published literature. However, results from this systematic analysis of published research provide positive evidence for the potential efficacy of TCZ to treat severe COVID-19, validating the ethical basis and merit of ongoing randomized controlled clinical trials.
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SciScore for 10.1101/2020.07.10.20150938: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. 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:Limitations: There are notable limitations to this systematic analysis and qualitative synthesis of TCZ. First, only one of the studies presented randomized who received TCZ, opening the possibility for selection bias and …
SciScore for 10.1101/2020.07.10.20150938: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. 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:Limitations: There are notable limitations to this systematic analysis and qualitative synthesis of TCZ. First, only one of the studies presented randomized who received TCZ, opening the possibility for selection bias and confounding factors that cannot be accounted for statistically. This systematic analysis synthesizes data from studies with different SOCs, geographies, resources, demographics, and TCZ dosing amount, number and timing. It is not possible to conclude that TCZ is efficacious in reducing COVID-19 mortality, simply that the data trends towards a lower odds ratio for mortality with incomplete generalizability. Similarly, while patients across all of the studies were at least in severe condition, the combined data still represents individuals at various stages of COVID-19. Not all of the studies offered a longitudinal time component, so an overall hazard ratio or Kaplan-Meir survival curve cannot be produced. Additionally, many patients were still in the hospital at the end of the observation period potentially skewing the mortality rate. Importantly, in the random effects odds ratio calculation, there was no control for age, sex and baseline characteristics like individual studies were able to accomplish. As noted, the uncontrolled trials on TCZ cannot be adequately evaluated without direct comparison to a control group. Finally, it is possible that studies finding a negative effect of TCZ were not published and not accounted for in this systematic review.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04322773 Terminated Anti-il6 Treatment of Serious COVID-19 Disease With Threaten… NCT04327388 Completed Sarilumab COVID-19 NCT04412772 Recruiting Trial of Tocilizumab for Treatment of Severe COVID-19: ARCHI… NCT04322188 Completed An Observational Study of the Use of Siltuximab (SYLVANT) in… NCT04280588 Withdrawn Fingolimod in COVID-19 NCT04280588 Withdrawn Fingolimod in COVID-19 NCT04409262 Active, not recruiting A Study to Evaluate the Efficacy and Safety of Remdesivir Pl… NCT04372186 Active, not recruiting A Study to Evaluate the Efficacy and Safety of Tocilizumab i… NCT04356937 Completed Efficacy of Tocilizumab on Patients With COVID-19 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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