Inflammatory Biomarkers and Exacerbations in Chronic Obstructive Pulmonary Disease
Inflammatory Biomarkers and Exacerbations in Chronic Obstructive Pulmonary Disease
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DOI：
10.1001/jama.2013.5732
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发表时间：
2013-06-12
影响因子：
120.7
通讯作者：
Nordestgaard, Borge G.
中科院分区：
文献类型：
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作者：
Thomsen, Mette;Ingebrigtsen, Truls Sylvan;Nordestgaard, Borge G.
重要性慢性阻塞性肺疾病（COPD）患者呼吸道症状的加重对患者有深远而持久的不良影响。目的检验稳定期COPD患者炎症生物标志物水平升高与呼吸道症状加重风险增加相关的假设。一项前瞻性队列研究，对哥本哈根城市心脏研究中的61650名参与者进行了肺功能测定（2001 - 2003年）和哥本哈根一般人口研究（2003-2008年）。其中，6574人患有COPD，定义为1秒用力呼气量（FEV 1）与用力肺活量之间的比值低于0.7。主要结果和测量在参与者没有出现急性加重症状时测量C反应蛋白（CRP）、纤维蛋白原和白细胞计数的基线水平。记录急性加重，并将其定义为口服皮质类固醇单独或联合抗生素的短期治疗或因COPD住院。CRP和纤维蛋白原水平以及白细胞计数分别根据3 mg/L、14 μ mol/L和9 × 10（9）/L的临界点被定义为高或低。在第一年的随访中，频繁急性加重的多变量调整优势比为1.2（95% CI，0.7-2.2; 17起事件/1000人-年），对于具有1个高生物标志物的个体，1.7（95% CI，0.9-3.2; 32起事件/1000人-年），对于具有2个高生物标志物的个体，和3.7（95% CI，1.9-7.4; 81起事件/1000人-年），与生物标志物未升高的个体相比（9起事件/1000人-年;趋势：P=2 x 10（-5））。使用最长随访时间的相应风险比分别为1.4（95% CI，1.1-1.8）、1.6（95% CI，1.3-2.2）和2.5（95% CI，1.8-3.4）（趋势：P=1 x 10（-8））。在包括年龄、性别、FEV 1预测百分比、吸烟、任何吸入性药物的使用、体重指数、既往急性发作史和距最近一次急性发作的时间的基础模型中添加炎症生物标志物，将C统计量从0.71改善至0.73（比较：P=9 x 10（-5））。轻度COPD患者、无频繁加重史患者以及2项单独研究中的相对风险一致。具有3个高生物标志物的患者中发生频繁加重的最高5年绝对风险慢性阻塞性肺疾病全球倡议（GOLD）C-D级患者（n=558）中的（vs无高生物标志物）为62%（vs 24%），有频繁急性加重史的患者（n=127）中为98%（vs 64%），GOLD 3-4级患者（n=465）为52%（vs15%）。结论和相关性COPD患者CRP、纤维蛋白原和白细胞计数水平同时升高与COPD急性加重风险增加相关，即使在轻度COPD患者和既往无急性加重的患者中也是如此。需要进一步的研究来确定这些生物标志物对危险分层的临床价值。
Importance Exacerbations of respiratory symptoms in chronic obstructive pulmonary disease (COPD) have profound and long-lasting adverse effects on patients.Objective To test the hypothesis that elevated levels of inflammatory biomarkers in individuals with stable COPD are associated with an increased risk of having exacerbations.Design, Setting, and Participants Prospective cohort study examining 61 650 participants with spirometry measurements from the Copenhagen City Heart Study (20012003) and the Copenhagen General Population Study (2003-2008). Of these, 6574 had COPD, defined as a ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity below 0.7.Main Outcomes and Measures Baseline levels of C-reactive protein (CRP) and fibrinogen and leukocyte count were measured in participants at a time when they were not experiencing symptoms of exacerbations. Exacerbations were recorded and defined as short-course treatment with oral corticosteroids alone or in combination with an antibiotic or as a hospital admission due to COPD. Levels of CRP and fibrinogen and leukocyte count were defined as high or low according to cut points of 3 mg/L, 14 mu mol/L, and 9 x 10(9)/L, respectively.Results During follow-up, 3083 exacerbations were recorded (mean, 0.5/participant). In the first year of follow-up, multivariable-adjusted odds ratios for having frequent exacerbations were 1.2 (95% CI, 0.7-2.2; 17 events/1000 person-years) for individuals with 1 high biomarker, 1.7 (95% CI, 0.9-3.2; 32 events/1000 person-years) for individuals with 2 high biomarkers, and 3.7 (95% CI, 1.9-7.4; 81 events/1000 person-years) for individuals with 3 high biomarkers compared with individuals who had no elevated biomarkers (9 events/1000 person-years; trend: P=2 x 10(-5)). Corresponding hazard ratios using maximum follow-up time were 1.4 (95% CI, 1.1-1.8), 1.6 (95% CI, 1.3-2.2), and 2.5 (95% CI, 1.8-3.4), respectively (trend: P=1 x 10(-8)). The addition of inflammatory biomarkers to a basic model including age, sex, FEV1 percent predicted, smoking, use of any inhaled medication, body mass index, history of previous exacerbations, and time since most recent prior exacerbation improved the C statistics from 0.71 to 0.73 (comparison: P=9 x 10(-5)). Relative risks were consistent in those with milder COPD, in those with no history of frequent exacerbations, and in the 2 studies separately. The highest 5-year absolute risks of having frequent exacerbations in those with 3 high biomarkers (vs no high biomarkers) were 62% (vs 24%) for those with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades C-D (n=558), 98% (vs 64%) in those with a history of frequent exacerbations (n=127), and 52% (vs 15%) for those with GOLD grades 3-4 (n=465).Conclusions and Relevance Simultaneously elevated levels of CRP and fibrinogen and leukocyte count in individuals with COPD were associated with increased risk of having exacerbations, even in those with milder COPD and in those without previous exacerbations. Further investigation is needed to determine the clinical value of these biomarkers for risk stratification.