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

Introduction 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 downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. 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 in a similar analysis. Results In the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, 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 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 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. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement FHs time was funded by the GW4 CAT Doctoral Fellowship scheme (Wellcome Trust, 222894/Z/21/Z). AHs time was funded by UCL British Heart Foundation Accelerator (AA/18/6/34223), the UCL NIHR Biomedical Research Centre, and the UKRI/NIHR funded Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1). AJM is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). PGs time was funded by the Welsh Government and the EU-ERDF (Ser Cymru Scheme). CS is supported by funding from National Institute for Health and Care Research (NIHR133788) and UKRI (MR/X005070/1). Her research programme is also supported by the Cambridge NIHR Biomedical Research Centre (BRC-1215-20014), the Wellcome Trust, and GlaxoSmithKline plc. NJT is a Wellcome Trust Investigator (202802/Z/16/Z) and works within the University of Bristol National Institute for Health Research (NIHR) Biomedical Research Centre (BRC). NJT is supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). The views expressed are those of the authors and not necessarily those of the NIHR, the NHS, or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Most of the data in this study was publicly available and non-identifiable. Therefore, no ethical approval was required to access it. Access to UK Biobank was arranged by the UK Biobank IDAC. This study was performed under application number 56243. UK Biobank has ethical approval details here (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data availability Most data used in this study are publicly available. For ease curated data (harmonised SNPs and MR results) are available at the authors GitHub (https://github.com/gushamilton/il6-sepsis) so all findings can be replicated. Raw data from the FinnGen GWAS are available via the FinnGen website (https://www.finngen.fi/) COVID-HGI GWAS are available via the COVID-HGI website (https://www.covid19hg.org/) and the UK Biobank GWAS performed as part of this study are available at the MRC-IEU Open GWAS repository (https://gwas.mrcieu.ac.uk/). Access to the full summary statistics for the sepsis GWAS performed by the GaINS and GenOSept committee is by application to the relevant committee. This research was performed under UK Biobank application 56243. Individual access to UK Biobank can be arranged via the UK Biobank website.