IL-6 inhibition in the treatment of COVID-19: a meta-analysis and meta-regression

Emmanuel Tharmarajah; April Buazon; Vishit Patel; Jennifer R Hannah; Maryam Adas; Victoria B Allen; Katie Bechman; Benjamin D Clarke; Deepak Nagra; Sam Norton; Mark D Russell; Andrew I Rutherford; Mark Yates; James B Galloway

doi:10.1016/j.jinf.2021.03.008

IL-6 inhibition in the treatment of COVID-19: a meta-analysis and meta-regression

Emmanuel Tharmarajah, April Buazon, Vishit Patel, Jennifer R Hannah, Maryam Adas, Victoria B Allen, Katie Bechman, Benjamin D Clarke, Deepak Nagra, Sam Norton, Mark D Russell, Andrew I Rutherford, Mark Yates, James B Galloway

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Abstract

Objectives: Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. Methods: Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. Results: Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I ² 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. Conclusions: IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

Original language	English
Pages (from-to)	178-185
Number of pages	8
Journal	Journal of Infection
Volume	82
Issue number	5
Early online date	18 Mar 2021
DOIs	https://doi.org/10.1016/j.jinf.2021.03.008
Publication status	Published - May 2021

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10.1016/j.jinf.2021.03.008

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@article{65dfeb1a4bf04555aa596285e7d76962,

title = "IL-6 inhibition in the treatment of COVID-19: a meta-analysis and meta-regression",

abstract = "Objectives: Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. Methods: Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. Results: Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I 2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. Conclusions: IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown. ",

author = "Emmanuel Tharmarajah and April Buazon and Vishit Patel and Hannah, {Jennifer R} and Maryam Adas and Allen, {Victoria B} and Katie Bechman and Clarke, {Benjamin D} and Deepak Nagra and Sam Norton and Russell, {Mark D} and Rutherford, {Andrew I} and Mark Yates and Galloway, {James B}",

note = "Funding Information: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. MDR and VBA receive funding from the National Institute for Health Research. BDC receives funding from Innovate UK. ET, AB, VP, JRH contributed equally to this work. Publisher Copyright: {\textcopyright} 2021 The British Infection Association Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = may,

doi = "10.1016/j.jinf.2021.03.008",

language = "English",

volume = "82",

pages = "178--185",

journal = "Journal of Infection",

issn = "0163-4453",

publisher = "British Infection Society",

number = "5",

}

TY - JOUR

T1 - IL-6 inhibition in the treatment of COVID-19

T2 - a meta-analysis and meta-regression

AU - Tharmarajah, Emmanuel

AU - Buazon, April

AU - Patel, Vishit

AU - Hannah, Jennifer R

AU - Adas, Maryam

AU - Allen, Victoria B

AU - Bechman, Katie

AU - Clarke, Benjamin D

AU - Nagra, Deepak

AU - Norton, Sam

AU - Russell, Mark D

AU - Rutherford, Andrew I

AU - Yates, Mark

AU - Galloway, James B

N1 - Funding Information: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. MDR and VBA receive funding from the National Institute for Health Research. BDC receives funding from Innovate UK. ET, AB, VP, JRH contributed equally to this work. Publisher Copyright: © 2021 The British Infection Association Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5

Y1 - 2021/5

N2 - Objectives: Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. Methods: Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. Results: Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I 2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. Conclusions: IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

AB - Objectives: Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. Methods: Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. Results: Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I 2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. Conclusions: IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

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U2 - 10.1016/j.jinf.2021.03.008

DO - 10.1016/j.jinf.2021.03.008

M3 - Article

C2 - 33745918

SN - 0163-4453

VL - 82

SP - 178

EP - 185

JO - Journal of Infection

JF - Journal of Infection

IS - 5

ER -

IL-6 inhibition in the treatment of COVID-19: a meta-analysis and meta-regression

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