肺功能正常吸烟者具有呼吸道症状能否当作COPD治疗？
2016/07/07
摘要
背景：目前，慢性阻塞性肺疾病（COPD）的诊断需要满足如下肺功能标准，即吸入支气管扩张药后第1秒用力呼气量(FEV1)与用力肺活量（FVC)的比值小于0.7。然而，许多吸烟者并没有达到这一标准，却仍然有明显的呼吸道症状。这类病人未能有效的管理。
方法：研究者进行了一项观察性研究，共纳入2736例患者，包括现吸烟或曾吸烟者以及从不吸烟的对照者，并且用 COPD评估试验（CAT；评分范围为0-40分，分数越高表明症状越严重）检测呼吸道症状。在吸入支气管扩张剂后FEV1/FVC ≥0.70和FVC >正常值范围的下限（本研究定义Preserved Pulmonary Function即认为肺功能正常）的现吸烟或曾吸烟者中，评估有症状(CAT评分≥10分)相比无症状 (CAT 评分<10分)组，是否具有更高的呼吸道症状急性加重的风险，比较两组是否在6分钟步行距离（6MWD）、肺功能或HRCT结果存在差别。
结果：在肺功能正常的现吸烟或曾吸烟者中，50%具有呼吸系统症状。有症状的现吸烟或曾吸烟者出现呼吸症状急性加重的平均比率(±SD)显著高于无症状的现吸烟或曾吸烟者和从不吸烟的对照者（每年分别发生0.27±0.67、0.08±0.31 和 0.03±0.21例事件；两两样本对比P<0.001)。不管是否有哮喘病史，与无症状的现吸烟或曾吸烟者相比，有症状的现吸烟或曾吸烟者有活动受限更明显， FEV1、FVC和深吸气量（IC）轻度下降，HRCT显示其气道壁增厚更显著，但无肺气肿表现。在有症状的现吸烟或曾吸烟者中，有42%的人使用支气管扩张剂，23%的人使用吸入糖皮质激素（ICS）。
结论：虽然有症状、肺功能正常的现吸烟或曾吸烟者不符合COPD的诊断标准，他们呼吸症状急性加重风险增加、存在更显著活动受限以及呼吸道疾病的证据。虽然他们正使用着一系列呼吸系统药物，目前没有任何证据基础。
评论：该研究通过纵向的研究发现，在肺功能正常的现吸烟或曾吸烟者中，50%存在明显呼吸系统症状。进一步发现这部分人出现呼吸症状急性发作的风险更大，6MWD较短，轻度肺功能下降以及气道壁增厚更加明显。该研究提示了平时通过肺量计的检测来确诊COPD的方法没有完全覆盖出现症状的吸烟相关的肺疾病患者。该结果证实并拓展了另一大型研究（Regan，2015），其结果提示超过50%的有症状状的吸烟者肺功能检查示正常，但具有显著的呼吸系统相关的损害和肺气肿表现。这两项研究提出了一个非常重要的研究问题，即吸烟相关疾病（smoking-induced disease），吸烟本身应当看作一种疾病，需要全面综合的管理。两项研究均证明，这类病人与轻至中度COPD具有相似的呼吸结局，两研究证实到一类复杂的临床综合征，临床实践中作为COPD对待，却不存在气流受限，这种综合征非常类似心衰，但射血分数无减损的情况。
GOLD指南COPD主要诊断标准为存在持续气流受限。然而临床实践中存在明显的局限性，目前临床上大多数可用的关于COPD的病理生理及管理的证据，均来自于根据肺功能评估存在气流受限的吸烟者。
这项研究提示FEV1在很多的吸烟者中并不是一个敏感指标，而只能作为吸烟者中某些亚群的早期诊断的工具。慢性支气管炎作为COPD的两个主要临床特征之一，存在于少数吸烟者中，提示全身症状，如胸闷，呼吸困难及能力受限可能更能代表吸烟的广泛效果
目前针对肺功能正常吸烟者的研究是缺乏的，进一步的临床研究将会给这些患者提供更好的治疗策略。
参考文献
1．Woodruff PG, Barr RG, Bleecker E，et al. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. N Engl J Med. 2016 May 12;374(19):1811-21.
BACKGROUND: Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms.
METHODS: We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest.
RESULTS: Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids.
CONCLUSIONS: Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base.
(Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.).
2．Leonardo M. Fabbri, M.D. Smoking, Not COPD, as the DiseaseN Engl J Med 2016; 374:1885-1886
3．Regan EA, Lynch DA, Curran-Everett D, et al. Clinical and radiologic disease in smokers with normal spirometry. JAMA Intern Med 2015; 175: 1539-49.
4．Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL,Redf ield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251-9.
背景：目前，慢性阻塞性肺疾病（COPD）的诊断需要满足如下肺功能标准，即吸入支气管扩张药后第1秒用力呼气量(FEV1)与用力肺活量（FVC)的比值小于0.7。然而，许多吸烟者并没有达到这一标准，却仍然有明显的呼吸道症状。这类病人未能有效的管理。
方法：研究者进行了一项观察性研究，共纳入2736例患者，包括现吸烟或曾吸烟者以及从不吸烟的对照者，并且用 COPD评估试验（CAT；评分范围为0-40分，分数越高表明症状越严重）检测呼吸道症状。在吸入支气管扩张剂后FEV1/FVC ≥0.70和FVC >正常值范围的下限（本研究定义Preserved Pulmonary Function即认为肺功能正常）的现吸烟或曾吸烟者中，评估有症状(CAT评分≥10分)相比无症状 (CAT 评分<10分)组，是否具有更高的呼吸道症状急性加重的风险，比较两组是否在6分钟步行距离（6MWD）、肺功能或HRCT结果存在差别。
结果：在肺功能正常的现吸烟或曾吸烟者中，50%具有呼吸系统症状。有症状的现吸烟或曾吸烟者出现呼吸症状急性加重的平均比率(±SD)显著高于无症状的现吸烟或曾吸烟者和从不吸烟的对照者（每年分别发生0.27±0.67、0.08±0.31 和 0.03±0.21例事件；两两样本对比P<0.001)。不管是否有哮喘病史，与无症状的现吸烟或曾吸烟者相比，有症状的现吸烟或曾吸烟者有活动受限更明显， FEV1、FVC和深吸气量（IC）轻度下降，HRCT显示其气道壁增厚更显著，但无肺气肿表现。在有症状的现吸烟或曾吸烟者中，有42%的人使用支气管扩张剂，23%的人使用吸入糖皮质激素（ICS）。
结论：虽然有症状、肺功能正常的现吸烟或曾吸烟者不符合COPD的诊断标准，他们呼吸症状急性加重风险增加、存在更显著活动受限以及呼吸道疾病的证据。虽然他们正使用着一系列呼吸系统药物，目前没有任何证据基础。
评论：该研究通过纵向的研究发现，在肺功能正常的现吸烟或曾吸烟者中，50%存在明显呼吸系统症状。进一步发现这部分人出现呼吸症状急性发作的风险更大，6MWD较短，轻度肺功能下降以及气道壁增厚更加明显。该研究提示了平时通过肺量计的检测来确诊COPD的方法没有完全覆盖出现症状的吸烟相关的肺疾病患者。该结果证实并拓展了另一大型研究（Regan，2015），其结果提示超过50%的有症状状的吸烟者肺功能检查示正常，但具有显著的呼吸系统相关的损害和肺气肿表现。这两项研究提出了一个非常重要的研究问题，即吸烟相关疾病（smoking-induced disease），吸烟本身应当看作一种疾病，需要全面综合的管理。两项研究均证明，这类病人与轻至中度COPD具有相似的呼吸结局，两研究证实到一类复杂的临床综合征，临床实践中作为COPD对待，却不存在气流受限，这种综合征非常类似心衰，但射血分数无减损的情况。
GOLD指南COPD主要诊断标准为存在持续气流受限。然而临床实践中存在明显的局限性，目前临床上大多数可用的关于COPD的病理生理及管理的证据，均来自于根据肺功能评估存在气流受限的吸烟者。
这项研究提示FEV1在很多的吸烟者中并不是一个敏感指标，而只能作为吸烟者中某些亚群的早期诊断的工具。慢性支气管炎作为COPD的两个主要临床特征之一，存在于少数吸烟者中，提示全身症状，如胸闷，呼吸困难及能力受限可能更能代表吸烟的广泛效果
目前针对肺功能正常吸烟者的研究是缺乏的，进一步的临床研究将会给这些患者提供更好的治疗策略。
（南方医科大学南方医院 赵文驱 赵海金审校）
参考文献
1．Woodruff PG, Barr RG, Bleecker E，et al. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. N Engl J Med. 2016 May 12;374(19):1811-21.
BACKGROUND: Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms.
METHODS: We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest.
RESULTS: Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids.
CONCLUSIONS: Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base.
(Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.).
2．Leonardo M. Fabbri, M.D. Smoking, Not COPD, as the DiseaseN Engl J Med 2016; 374:1885-1886
3．Regan EA, Lynch DA, Curran-Everett D, et al. Clinical and radiologic disease in smokers with normal spirometry. JAMA Intern Med 2015; 175: 1539-49.
4．Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL,Redf ield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251-9.
