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

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.

Clozapine treatment and risk of COVID-19.

The antipsychotic clozapine is known to have immune-modulating effects. Clozapine treatment has been reported to be associated with increased risk of COVID-19 infection. However, it remains unclear whether this is because of increased testing of this patient group, who are closely monitored. We linked anonymised health records from mental health services in Cambridgeshire (UK), for patients taking antipsychotic medication, with data from the local COVID-19 testing hub. Patients receiving clozapine were more likely to be tested for COVID-19, but not to test positive. Increased testing in patients receiving clozapine suggests prudent judgement by clinicians, considering the overall health vulnerabilities of this group.

Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19.

The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety. We propose that neuroimmune cross-talk via inflammatory cytokines such as interleukin-6 (IL-6) could underpin these long-term COVID-19 symptoms. This hypothesis is supported by several lines of research, including population-based cohort and genetic Mendelian Randomisation studies suggesting that inflammation is associated with fatigue and sleeping difficulties, and that IL-6 could represent a possible causal driver for these symptoms. Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic.