Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.
Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.
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DOI：
10.1371/journal.pmed.1004174
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发表时间：
2023-01
期刊：
影响因子：
15.8
通讯作者：
中科院分区：
文献类型：
--
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脓毒症的特点是免疫反应失调，危及生命，被认为是由白细胞介素6 （IL-6）等细胞因子驱动的。已知下调IL-6信号的IL6R遗传变异与2019冠状病毒病（COVID-19）预后的改善有关，这一发现后来在IL-6受体拮抗剂（IL6RAs）的随机试验中得到证实。我们假设阻断IL6R也可以改善败血症的预后。我们使用IL6R内和附近的单核苷酸多态性（snp）进行了孟德尔随机化（MR）分析，以评估IL6R阻断对败血症（主要结局）、败血症严重程度、其他感染和COVID-19（次要结局）的可能因果影响。我们根据snp对CRP的影响对其进行加权，并在逆方差加权荟萃分析中综合它们的结果，代表IL6RA的影响。我们的结果在UK Biobank、FinnGen、COVID-19宿主遗传学计划（HGI）以及GenOSept和GainS联盟中进行了测量。我们进行了一些敏感性分析来检验我们方法的假设，包括在类似的分析中使用CRP和gp130的变体。在英国生物银行队列（N = 486,484，包括11,643例败血症）中，IL6R阻断与我们的主要结局败血症风险降低相关(优势比(OR) = 0.80；95%置信区间（CI） 0.66至0.96，每单位自然对数转换CRP下降)。这种影响的大小随着严重程度的增加而增加，对28天脓毒症死亡率的影响更大（OR = 0.74; 95% CI 0.47至1.15）；重症监护住院败血症（OR = 0.48, 95% CI 0.30至0.78）和重症监护死亡败血症（OR = 0.37, 95% CI 0.14至0.98）。在严重呼吸道感染中也发现了类似的关联：在gain和GenOSept联合研究中，重症监护肺炎的OR为0.69 (95% CI 0.49至0.97)，重症监护败血症生存的OR为0.22 (95% CI 0.04至1.31)，尽管这一结果存在很大程度的不精确性。我们还证实了先前报道的il - 6r阻断对COVID-19 HGI中严重COVID-19的保护作用（OR = 0.69, 95% CI 0.57至0.84），其程度与败血症相似。敏感性分析没有改变我们的主要结果。这些结果受限于MR的局限性和假设，在这种情况下，MR反映了这些SNP效应的解释，即通过阻断IL6R产生因果作用，并且反映了终生暴露于IL6R阻断，而不是治疗性IL6R阻断的效果。IL6R阻断与脓毒症发生率降低有因果关系。类似但不精确的估计结果也支持脓毒症相关死亡率和脓毒症重症监护住院的因果效应。这些效果在大小上与严重的COVID-19所见的效果相当，在严重的COVID-19中，IL-6受体拮抗剂被证明可以提高生存率。这些数据表明，应该考虑在败血症中使用IL-6受体拮抗剂进行随机试验。在孟德尔随机分析中，Fergus Hamilton和他的同事验证了阻断白细胞介素-6信号传导可以改善败血症结果的假设。使用托珠单抗等与IL-6受体结合的药物抑制细胞因子白细胞介素6 (IL-6)，已被证明可以降低2019年冠状病毒病（COVID-19）重症患者的死亡率。目前尚不清楚IL-6抑制是否对其他严重感染（如细菌性败血症）也有类似的益处。遗传分析（孟德尔随机化（MR））先前预测了IL-6抑制在COVID-19和其他疾病中的成功。在一项大型英国队列研究中（N = 485,825，包括11,643例败血症患者），遗传变异作为IL6R阻断的代理（或自然实验）与败血症的发生率降低相关(优势比（or） 0.80；95%可信区间（CI） 0.66 ~ 0.96)。在二级队列中，当使用不同的脓毒症定义时，效果是一致的，在更严重的表型中，效应大小通常更大。对脓毒症的影响估计与严重COVID-19相似（OR 0.69, 95% CI 0.57至0.84），目前推荐使用IL-6阻断剂。在MR的限制和假设下，这些发现支持在脓毒症的随机对照试验中考虑IL-6抑制。更广泛地说，这些发现支持IL-6在严重感染中的潜在病理作用。
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. 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. 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. In a Mendelian randomisation analysis, Fergus Hamilton and colleagues test the hypothesis that blockade of interleukin-6 signalling could improve outcomes in sepsis. Inhibition of the cytokine interleukin 6 (IL-6) using drugs such as tocilizumab, which bind to the IL-6 receptor, has been shown to reduce mortality in critically unwell patients with Coronavirus Disease 2019 (COVID-19). It is currently unknown whether IL-6 inhibition might have similar benefits in other, severe infections, such as bacterial sepsis. Genetic analyses (Mendelian randomisation (MR)) have previously predicted the success of IL-6 inhibition in COVID-19 and other conditions. In a large, UK cohort (N = 485,825, including 11,643 with sepsis), genetic variation acting as a proxy (or natural experiment) for IL6R blockade was associated with a reduced odds of sepsis (odds ratio (OR) 0.80; 95% confidence interval (CI) 0.66 to 0.96) in MR analyses. Effects were consistent in secondary cohorts and when using differing definitions of sepsis, with effect sizes generally larger in more severe phenotypes. The effect estimates on sepsis were similar in magnitude to those seen in severe COVID-19 (OR 0.69, 95% CI 0.57 to 0.84), where IL-6 blockade is currently recommended. Within the limitations and assumptions of MR, these findings support the consideration of IL-6 inhibition in randomised controlled trials in sepsis. More broadly, these findings support the potentially pathological role of IL-6 in severe infection.
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影响因子：
11
作者：
Khandaker, Golam M.;Zuber, Verena;Burgess, Stephen
通讯作者：
Burgess, Stephen
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
15.8
作者：
Gill D;Burgess S
通讯作者：
Burgess S
DOI：
10.1016/s2665-9913(20)30345-3
发表时间：
2020-11
期刊：
The Lancet. Rheumatology
影响因子：
--
作者：
Bovijn J;Lindgren CM;Holmes MV
通讯作者：
Holmes MV
影响因子：
4.5
作者：
Ferreira RC;Freitag DF;Cutler AJ;Howson JM;Rainbow DB;Smyth DJ;Kaptoge S;Clarke P;Boreham C;Coulson RM;Pekalski ML;Chen WM;Onengut-Gumuscu S;Rich SS;Butterworth AS;Malarstig A;Danesh J;Todd JA
通讯作者：
Todd JA