Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.
Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.
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DOI：
10.1016/s2213-2600(16)30048-0
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发表时间：
2016-07
影响因子：
76.2
通讯作者：
Fahy, John V.
中科院分区：
文献类型：
--
作者：
Peters, Michael C.;McGrath, Kelly Wong;Hawkins, Gregory A.;Hastie, Annette T.;Levy, Bruce D.;Israel, Elliot;Phillips, Brenda R.;Mauger, David T.;Comhair, Suzy A.;Erzurum, Serpil C.;Johansson, Mats W.;Jarjour, Nizar N.;Coverstone, Andrea M.;Castro, Mario;Holguin, Fernando;Wenzel, Sally E.;Woodruff, Prescott G.;Bleecker, Eugene R.;Fahy, John V.
严重哮喘是一种复杂的异质性疾病，与老年和肥胖有关。嗜酸性粒细胞（2型）炎症的存在，在一些但不是所有的严重哮喘患者预测目前的治疗反应，但新的治疗方法将需要更好地了解严重哮喘的非2型机制。我们考虑了全身性炎症的可能性--发生在肥胖和老年患者的亚组中--改变哮喘使其恶化。白细胞介素6（IL 6）是全身炎症和代谢功能障碍的生物标志物，本研究旨在探讨IL 6、代谢功能障碍与哮喘严重程度的关系。我们在健康对照组（n=93）中产生了血浆IL 6的健康参考范围。我们比较了两个哮喘队列中血浆IL 6水平低于和高于正常上限（“IL 6低”和“IL-高”哮喘）的哮喘患者的临床特征-主要是加州大学弗朗西斯科分校（UCSF）招募的非重度哮喘患者（n=249）和严重哮喘研究计划（SARP）招募的主要重度哮喘患者（n=387）。健康队列中血浆IL 6的第95百分位数上限值为3.1pg/mL，14%的UCSF队列和26%的SARP队列的血浆IL 6水平高于该上限。两个哮喘组群中的“IL 6高”患者比IL 6低患者具有显著更高的体重指数和更高的代谢疾病患病率（所有p值< 0.01）。与IL 6低患者相比，IL 6高患者的肺功能也显著降低，哮喘急性发作更频繁（所有p值均<0.01）。虽然75%的IL-6高哮喘患者肥胖，但63%的肥胖患者IL-6低。在肥胖患者中，IL 6高水平患者的1秒用力呼气量（FEV 1）显著低于IL 6低水平患者（平均FEV 1 70·8 [S.D. 19·5] vs. 78·1 [19·7] %预测值，p = 0·002），并且在过去1-2年中报告哮喘急性发作的患者百分比在IL 6高患者中高于IL 6低患者（66 vs. 48%，p = 0·003）。在非肥胖哮喘患者中，IL 6高水平患者的FEV1%和哮喘急性发作结局也显著差于IL 6低水平患者（平均FEV 166·4 [SD 23·1] vs. 83·2 [20·4] %预测值，p< 0·01; 59 vs. 34%，p=0·008）。全身性IL 6炎症和代谢功能障碍的临床特征-最常见于肥胖哮喘患者的子集中，但也存在于非肥胖患者的小子集中-与更严重的哮喘相关。改善代谢功能障碍的IL 6抑制剂或治疗代表了对严重哮喘患者子集进行的合理临床试验，血浆IL 6是可以指导患者分层的生物标志物。
Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts responsiveness to current treatments, but new treatment approaches will require better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation - which occurs in subgroups of obese and older patients - modifies asthma to make it worse. Interleukin 6 (IL6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the relationship between IL6, metabolic dysfunction, and asthma severity. We generated a reference range in health for plasma IL6 in a cohort of healthy controls (n=93). We compared the clinical characteristics of asthmatics with plasma IL6 levels below and above the upper limit of normal (“IL6 low” and “IL-high” asthma) in two asthma cohorts - predominantly non-severe asthmatics recruited at the University of California San Francisco (UCSF)(n=249) and predominantly severe asthmatics recruited by the Severe Asthma Research Program (SARP)(n=387). The upper 95th centile value for plasma IL6 in the healthy cohort was 3·1pg/mL, and 14% of UCSF cohort and 26% of the SARP cohort had plasma IL6 levels above this upper limit. The “IL6-high” patients in both asthma cohorts had a significantly higher body mass index and a higher prevalence of metabolic disease than the IL6-low patients (all p values < 0.01). IL6-high patients also had significantly lower lung function and more frequent asthma exacerbations than IL6-low patients (all p values < 0·01). Although 75% of IL6-high asthmatics were obese, 63% of obese patients were IL6-low. Among obese patients, the forced expired volume in one second (FEV1) was significantly lower in IL6-high than in IL6-low patients (mean FEV1 70·8 [S.D. 19·5] vs. 78·1 [19·7] % predicted, p = 0·002), and the percentage of patients reporting an asthma exacerbation in the past 1-2 years was higher in IL6-high than in IL6-low patients (66 vs. 48%, p = 0·003). Among non-obese asthmatics, FEV1% and asthma exacerbation outcomes were also significantly worse in IL6-high than in IL6-low patients (mean FEV1 66·4 [SD 23·1] vs. 83·2 [20·4] % predicted, p< 0·01; 59 vs. 34 %, p=0·008). Systemic IL6 inflammation and clinical features of metabolic dysfunction - occurring most commonly among a subset of obese asthmatics but also in a small subset of non-obese patients - is associated with more severe asthma. IL6 inhibitors or treatments that improve metabolic dysfunction represent rational clinical trials to pursue for a subset of patients with severe asthma, and plasma IL6 is a biomarker that could guide patient stratification.