Current Evidence of Interleukin-6 Signaling Inhibitors in Patients With COVID-19: A Systematic Review and Meta-Analysis

Qi Han; Mingyue Guo; Yue Zheng; Ying Zhang; Yanshan De; Changchang Xu; Lin Zhang; Ruru Sun; Ying Lv; Yan Liang; Feng Xu; Jiaojiao Pang; Yuguo Chen

doi:10.3389/fphar.2020.615972

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.

Authors

Qi Han^{1

2

3

4}, Mingyue Guo^{1

2

3

4}, Yue Zheng^{1

2

3

4}, Ying Zhang^{1

2

3

4}, Yanshan De^{1

2

3

4}, Changchang Xu^{1

2

3

4}, Lin Zhang^{1

2

3

4}, Ruru Sun^{1

2

3

4}, Ying Lv^{1

2

3

4}, Yan Liang^{1

2

3

4}, Feng Xu^{1

2

3

4}, Jiaojiao Pang^{1

2

3

4}, Yuguo Chen^{1

2

3

4}

Affiliations

¹ Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China.
² Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China.
³ Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
⁴ The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China.

Abstract

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 (clinicaltrials.gov), 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.

Keywords: COVID-19; ICU admission; anti-IL-6 signaling agents; clinical improvement; mechanical ventilation; mortality; secondary infections.

Publication types

Review