COVID-19 Evidence Alerts
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Treatment Han Q, Guo M, Zheng Y, et al. Current Evidence of Interleukin-6 Signaling Inhibitors in Patients With COVID-19: A Systematic Review and Meta-Analysis. Front Pharmacol. 2020 Dec 15;11:615972. doi: 10.3389/fphar.2020.615972. eCollection 2020.

Background: Interleukin-6 (IL-6) is known to be detrimental in coronavirus disease 2019 (COVID-19) because of its involvement in driving cytokine storm. This systematic review and meta-analysis aimed to assess the safety and efficacy of anti-IL-6 signaling (anti-IL6/IL-6R/JAK) agents on COVID-19 based on the current evidence. Methods: Studies were identified through systematic searches of PubMed, EMBASE, ISI Web of Science, Cochrane library, ongoing clinical trial registries (, and preprint servers (medRxiv, ChinaXiv) on August 10, 2020, as well as eligibility checks according to predefined selection criteria. Statistical analysis was performed using Review Manager (version 5.3) and STATA 12.0. Results: Thirty-one studies were included in the pooled analysis of mortality, and 12 studies were identified for the analysis of risk of secondary infections. For mortality analysis, 5630 COVID-19 cases including 2,132 treated patients and 3,498 controls were analyzed. Anti-IL-6 signaling agents plus standard of care (SOC) significantly decreased the mortality rate compared to SOC alone (pooled OR = 0.61, 95% CI 0.45-0.84, p = 0.002). For the analysis of secondary infection risk, 1,624 patients with COVID-19 including 639 treated patients and 985 controls were included, showing that anti-IL-6 signaling agents did not increase the rate of secondary infections (pooled OR = 1.21, 95% CI 0.70-2.08, p = 0.50). By contrast, for patients with critical COVID-19 disease, anti-IL-6 signaling agents failed to reduce mortality compared to SOC alone (pooled OR = 0.75, 95% CI 0.42-1.33, p = 0.33), but they tended to increase the risk of secondary infections (pooled OR = 1.85, 95% CI 0.95-3.61, p = 0.07). A blockade of IL-6 signaling failed to reduce the mechanical ventilation rate, ICU admission rate, or elevate the clinical improvement rate. Conclusion: IL-6 signaling inhibitors reduced the mortality rate without increasing secondary infections in patients with COVID-19 based on current studies. For patients with critical disease, IL-6 signaling inhibitors did not exhibit any benefit.

Discipline / Specialty Area Score
Infectious Disease
Intensivist/Critical Care
Comments from MORE raters

Infectious Disease rater

The systematic review is comprehensive and updated. However, I strongly disagree with the conclusions of the meta-analysis for several reasons: 1. There is a combination of several observational studies (cohorts and case control) with one experimental design. 2. There is a combination of interventions with different profiles (there is no one “single anti-IL-6 agents”). 3. There is important statistical heterogeneity (I2 73%, reduced to 53% after data dredging with ad-hoc exclusion of the Martinez-Sand´s study). 4. There is incomplete quality assessment (“we found that all the controlled studies were of satisfactory high quality for metaanalysis”) because most of the studies had important failures in confounding adjustment. 5. The conclusions are not supported by the data.

Intensivist/Critical Care rater

The recent results of the The REMAP-CAP Investigators, "Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report", are not included in this metanalysis. Perhaps, with COVID knowledge growing rapidly, this paper is already old news.

Respirology/Pulmonology rater

At least, this is a systematic review with a definite conclusion.