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Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis.
Clin Microbiol Infect. 2021 Feb; 27(2):215-227.CM

Abstract

OBJECTIVES

Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to perform a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients.

METHODS

Data sources were Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google up to October 8, 2020. Study eligibility criteria were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs and adjusted RRs from cohorts, separately. We evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach.

RESULTS

Of 1156 citations, 24 studies were eligible (five RCTs and 19 cohorts). Five RCTs at low risk of bias, with 1325 patients, examined the effect of tocilizumab on short-term mortality; pooled RR was 1.09 (95%CI 0.80-1.49, I2 = 0%). Four RCTs with 771 patients examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.71 (95%CI 0.52-0.96, I2 = 0%), with a corresponding number needed to treat of 17 (95%CI 9-100). Among 18 cohorts at moderate risk of bias with 9850 patients, the pooled adjusted RR for mortality was 0.58 (95%CI 0.51-0.66, I2 = 2.5%). This association was observed over all degrees of COVID-19 severity. Data from the RCTs did not show a higher risk of infections or adverse events with tocilizumab: pooled RR 0.63 (95%CI 0.38-1.06, five RCTs) and 0.83 (95%CI 0.55-1.24, five RCTs), respectively.

CONCLUSIONS

Cumulative moderate-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized COVID-19 patients. While RCTs showed that tocilizumab did not reduce short-term mortality, low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality. We did not observe a higher risk of infections or adverse events with tocilizumab use. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment.

Authors+Show Affiliations

Infectious Diseases Section, Department of Medical Specialties King Fahad Medical City, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Division of Infectious Diseases, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; Division of Epidemiology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. Electronic address: Tleyjeh.Imad@mayo.edu.Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.Division of Hematology and HSCT, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia; King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.Department of Public Health, College of Health Sciences, Qatar University, Doha, Qatar.King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; Department of Intensive Care, King Abdulaziz Medical City, Riyadh, Saudi Arabia.College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.Research Center, King Fahad Medical City, Riyadh, Saudi Arabia.College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA.Department of Cardiac Sciences, King Fahad Cardiac Center, King Saud University Medical City, Riyadh, Saudi Arabia.

Pub Type(s)

Journal Article
Meta-Analysis
Systematic Review

Language

eng

PubMed ID

33161150

Citation

Tleyjeh, Imad M., et al. "Efficacy and Safety of Tocilizumab in COVID-19 Patients: a Living Systematic Review and Meta-analysis." Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, vol. 27, no. 2, 2021, pp. 215-227.
Tleyjeh IM, Kashour Z, Damlaj M, et al. Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis. Clin Microbiol Infect. 2021;27(2):215-227.
Tleyjeh, I. M., Kashour, Z., Damlaj, M., Riaz, M., Tlayjeh, H., Altannir, M., Altannir, Y., Al-Tannir, M., Tleyjeh, R., Hassett, L., & Kashour, T. (2021). Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis. Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, 27(2), 215-227. https://doi.org/10.1016/j.cmi.2020.10.036
Tleyjeh IM, et al. Efficacy and Safety of Tocilizumab in COVID-19 Patients: a Living Systematic Review and Meta-analysis. Clin Microbiol Infect. 2021;27(2):215-227. PubMed PMID: 33161150.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis. AU - Tleyjeh,Imad M, AU - Kashour,Zakariya, AU - Damlaj,Moussab, AU - Riaz,Muhammad, AU - Tlayjeh,Haytham, AU - Altannir,Mustafa, AU - Altannir,Youssef, AU - Al-Tannir,Mohamad, AU - Tleyjeh,Rana, AU - Hassett,Leslie, AU - Kashour,Tarek, Y1 - 2020/11/05/ PY - 2020/10/01/received PY - 2020/10/26/revised PY - 2020/10/29/accepted PY - 2020/11/9/pubmed PY - 2021/2/26/medline PY - 2020/11/8/entrez KW - COVID-19 KW - Meta-analysis KW - Mortality KW - Tocilizumab KW - Toxicity SP - 215 EP - 227 JF - Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases JO - Clin Microbiol Infect VL - 27 IS - 2 N2 - OBJECTIVES: Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to perform a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients. METHODS: Data sources were Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google up to October 8, 2020. Study eligibility criteria were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs and adjusted RRs from cohorts, separately. We evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach. RESULTS: Of 1156 citations, 24 studies were eligible (five RCTs and 19 cohorts). Five RCTs at low risk of bias, with 1325 patients, examined the effect of tocilizumab on short-term mortality; pooled RR was 1.09 (95%CI 0.80-1.49, I2 = 0%). Four RCTs with 771 patients examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.71 (95%CI 0.52-0.96, I2 = 0%), with a corresponding number needed to treat of 17 (95%CI 9-100). Among 18 cohorts at moderate risk of bias with 9850 patients, the pooled adjusted RR for mortality was 0.58 (95%CI 0.51-0.66, I2 = 2.5%). This association was observed over all degrees of COVID-19 severity. Data from the RCTs did not show a higher risk of infections or adverse events with tocilizumab: pooled RR 0.63 (95%CI 0.38-1.06, five RCTs) and 0.83 (95%CI 0.55-1.24, five RCTs), respectively. CONCLUSIONS: Cumulative moderate-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized COVID-19 patients. While RCTs showed that tocilizumab did not reduce short-term mortality, low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality. We did not observe a higher risk of infections or adverse events with tocilizumab use. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment. SN - 1469-0691 UR - https://www.unboundmedicine.com/medline/citation/33161150/Efficacy_and_safety_of_tocilizumab_in_COVID_19_patients:_a_living_systematic_review_and_meta_analysis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1198-743X(20)30690-X DB - PRIME DP - Unbound Medicine ER -