Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study

Abstract

Background: Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.

Methods and findings: We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.

Conclusions: IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Fig 1. Section A represents a randomised trial of IL6RA therapy with both normal IL-6 signalling and the effect of intervention.

Section B represents the use of SNPs in IL6R to act as a proxy for intervention. We identify variants within IL6R associated with reduced CRP as a marker of functional IL6R blockade to aid the interpretation of MR analysis. As these SNPs are within IL6R, we make the assumption that these SNPs have an effect through alteration of IL6R (either through modification of the protein itself or altering quantity of the protein). Image made using Biorender.com. ADAM17, A disintegrin and metalloprotease 17; CRP, C-reactive protein; GP130, Glycoprotein 130; IL-6, interleukin 6; IL6R, interleukin 6 receptor, IL6RA, interleukin 6 receptor antagonist; IL6R (m), modified interlekin 6 receptor; MR, Mendelian randomisation; sIL6R, soluble interleukin 6 receptor; SNP, single nucleotide polymorphism.

Fig 2

IVW MR estimates (ORs) with 95% CIs for IL6R blockade and each outcome (A: Sepsis, B: COVID, C: other infections) in UK Biobank. CI, confidence interval; COVID-19, Coronavirus Disease 2019; IVW, inverse variance weighted; LRTI, lower respiratory tract infection; MR, Mendelian randomisation; OR, odds ratio; URTI, upper respiratory tract infection; UTI, urinary tract infection.

Fig 3

IVW MR estimates of IL6R blockade with 95% CIs for (A) respiratory infection, (B) survival from sepsis related to critical care admission, and (C) FinnGen replication cohort. CI, confidence interval; IVW, inverse variance weighted; LRTI, lower respiratory tract infection; MR, Mendelian randomisation; OR, odds ratio; URTI, upper respiratory tract infection; UTI, urinary tract infection.

Fig 4

IVW MR effect estimates for CRP from cisCRP variants and each outcome (A: Sepsis, B: COVID, C: other infections). CI, confidence interval; COVID-19, Coronavirus Disease 2019; CRP, C-reactive protein; IVW, inverse variance weighted; LRTI, lower respiratory tract infection; MR, Mendelian randomisation; OR, odds ratio; URTI, upper respiratory tract infection; UTI, urinary tract infection.