臺灣博碩士論文加值系統

背景與目的：慢性阻塞性肺病 (chronic obstructive pulmonary disease, COPD) 是世界常見的慢性病和主要的死亡原因之一，造成嚴重的經濟負擔。透過電腦斷層掃描發現慢性阻塞性肺病患者中有高比例的支氣管擴張症盛行率，特別是中至重度患者。慢性阻塞性肺病和支氣管擴張症具有許多共同特徵，包括慢性咳嗽以及不完全可逆的呼吸道阻塞。過去研究顯示支氣管擴張症和較嚴重的呼吸道阻塞、較頻繁的急性惡化、以及較高的死亡風險有相關。共存的慢性阻塞性肺病和支氣管擴張症代表獨特的臨床表現，具有較差預後。針對台灣的慢性阻塞性肺病患者，尚無資料顯示合併支氣管擴張症對急性惡化率的影響，也缺乏評估慢性阻塞性肺病合併支氣管擴張症患者治療策略的研究。因此，本研究目的為探討共存的支氣管擴張症對慢性阻塞性肺病急性惡化與死亡之影響，以及評估在這個共病症族群其藥物的治療效果。
方法：本研究設計為回溯性世代研究 (retrospective cohort study)，使用2000至2011年台灣全民健康保險研究資料庫的資料，收錄2000至2009年間新診斷、年齡在40歲以上且有用藥的慢性阻塞性肺病患者。接著從中挑選新診斷的支氣管擴張症患者作為暴露世代，定義第一次診斷日期為指標日期，並排除診斷前未進行胸部X光及電腦斷層掃描檢查者。依年齡 (±2歲)、性別及指標年份以1:4比例配對適當的非支氣管擴張症病人即為對照世代。 所有病人皆追蹤至死亡、退保、或研究期間結束 (2011年12月31日)，並記錄病患急性惡化的頻率以及急性惡化的藥物治療。以COX比例風險模型分析支氣管擴張症對急性惡化及死亡的風險之影響，以及評估支氣管擴張劑及具潛在抗發炎效果之藥物對慢性阻塞性肺病合併支氣管擴張症患者急性惡化風險之影響。
結果：本研究共收錄4,152位慢性阻塞性肺病病人，其中有831位合併支氣管擴張症，3,321位未合併支氣管擴張症。研究期間慢性阻塞性肺病合併支氣管擴張症之患者有較高的中至重度及重度急性惡化率，率比 (rate ratio) 分別為3.42 (95% 信賴區間 [confidence interval, CI], 3.17-3.68; P < 0.0001) 及3.14 (95% CI, 2.72-3.61; P < 0.0001)。再者，多變項COX迴歸分析顯示，相較於未合併支氣管擴張症患者，合併支氣管擴張症患者中至重度急性惡化風險比 (hazard ratio, HR) 為2.17 (95% CI, 1.85-2.53; P < 0.0001)、重度急性惡化風險比為1.81 (95% CI, 1.46-2.25; P < 0.0001) 及死亡風險比為1.47 (95% CI, 1.24-1.73; P < 0.0001)。此外，對於慢性阻塞性肺病合併支氣管擴張症之患者而言，若使用長效型毒蕈鹼拮抗劑及茶鹼類衍生物相較於未使用者，校正後急性惡化風險比分別為2.37 (95% CI, 1.33-4.21; P = 0.0033) 及2.00 (95% CI, 1.52-2.63; P < 0.0001)，然而，併用mucolytic agents及statins相較於未使用者，校正後急性惡化風險比分別為0.49 (95% CI, 0.38-0.63; P < 0.0001) 及0.40 (95% CI, 0.27-0.60; P < 0.0001)。
結論：慢性阻塞性肺病合併支氣管擴張症和較頻繁及嚴重的急性惡化、以及較高的死亡風險有關。針對慢性阻塞性肺病合併支氣管擴張症之患者，併用mucolytic agents或statins和較低的急性惡化風險有關。未來仍需更多前瞻性研究確認支氣管擴張劑及具潛在抗發炎效果之藥物對慢性阻塞性肺病合併支氣管擴張症患者的治療效果。

Background: Chronic obstructive pulmonary disease (COPD) accounts for a leading cause of morbidity and mortality in the world which brings about a significant economic burden. A high prevalence of bronchiectasis is identified by computed tomography (CT) among patients with COPD, especially in moderate-to-severe stages. COPD and bronchiectasis share many characteristics, including chronic cough and incompletely reversible airway obstruction. Previous studies have shown the presence of bronchiectasis is associated with more severe airway obstruction, more frequent exacerbations, and an increased risk of mortality. Coexisting COPD and bronchiectasis may represent a distinct phenotype which may have an implication for worse prognosis. However, no data has assessed the effect of bronchiectasis on exacerbation rates in patients with COPD in Taiwan. Studies to evaluate the treatment strategies for patients with COPD and bronchiectasis are also lacking. Therefore, the aim of this study was to investigate the influence of coexisting bronchiectasis on COPD exacerbations and mortality and evaluate the effect of its treatment in patients with COPD and bronchiectasis.
Method: We conducted a retrospective cohort study using data from the Taiwan National Health Insurance Research Database between 2000 and 2011. The newly diagnosed COPD patients who aged 40 years and older and received COPD medications from 2000 to 2009 were identified. In the COPD cohort, patients were diagnosed with bronchiectasis as the exposure cohort, and the first diagnosis date was defined as the index date. Patients without performing chest X-ray or CT prior to diagnosis of bronchiectasis were excluded. The comparison cohort was matched from those COPD patients without bronchiectasis at a 1:4 ratio, according to age (±2 years), sex, and the index year. Patients were followed until death, termination of health insurance coverage, or December 31, 2011. The frequency of exacerbations and treatment during exacerbations were recorded. COX proportional hazard regression was used to analyze the risk of acute exacerbation and mortality for bronchiectasis, and evaluate the effect of bronchodilators and treatment with anti-inflammatory potential on the risk of exacerbation for patients with bronchiectasis and COPD.
Results: A total of 4,152 subjects were included. Among them, 831 COPD patients with newly diagnosed bronchiectasis were identified, and 3,321 COPD patients without bronchiectasis were matched. During the follow-up period, the rate of moderate-to-severe and severe exacerbations were more frequent in patients with bronchiectasis than in those without bronchiectasis, with rate ratios of 3.42 (95% confidence interval [CI], 3.17-3.68; P < 0.0001) and 3.14 (95% CI, 2.72-3.61; P < 0.0001), respectively. Furthermore, the mutivariable Cox regression analysis revealed that the presence of bronchiectasis was independently associated with increased risks of moderate-to-severe exacerbation (hazard ratio [HR], 2.17; 95% CI, 1.85-2.53; P < 0.0001), severe exacerbation (HR, 1.81; 95% CI, 1.46-2.25; P < 0.0001) and mortality (HR, 1.47; 95% CI, 1.24-1.73; P < 0.0001). In addition, among patients with coexisting bronchiectasis and COPD, the adjusted HR for exacerbations in patients using long-acting muscarinic antagonist (LAMA) was 2.37 (95% CI, 1.33-4.21; P = 0.0033) and in patients using methylxanthines was 2.00 (95% CI, 1.52-2.63; P < 0.0001), but the adjusted HR for exacerbations in patients taking co-medication with mucolytic agents and statins was 0.49 (95% CI, 0.38-0.63; P < 0.0001) and 0.40 (95% CI, 0.27-0.60; P < 0.0001), respectively.
Conclusion: The presence of bronchiectasis in patients with COPD was associated with more frequent and severe exacerbations, and increased risks of mortality. Among patients with coexisting bronchiectasis and COPD, taking co-medication with mucolytic agents or statins was associated with decreased risk of exacerbation. Further prospective studies are warranted to confirm the effect of bronchodilators and treatment with anti-inflammatory potential in patients with bronchiectasis and COPD.

目錄
中文摘要 I
英文摘要 III
目錄 VI
圖目錄 VIII
表目錄 IX
縮寫表 X
第一章 緒論 1
第一節 研究背景與動機 1
第二節 研究目的 29
第二章 文獻探討 30
第三章 研究方法與設計 36
第一節 研究項目與研究假設 36
第二節 研究設計與研究工具 37
第三節 統計方法 54
第四章 研究結果 57
第一節 研究族群基本特性 57
第二節 支氣管擴張症與急性惡化及死亡風險的相關性 67
第三節 支氣管擴張劑與急性惡化風險的相關性 78
第四節 Macrolides、mucolytic agents及statins 與急性惡化風險的相關性 80
第五章 討論 83
第一節 研究族群基本特性 83
第二節 支氣管擴張症與急性惡化及死亡風險的相關性 89
第三節 支氣管擴張劑與急性惡化風險的相關性 93
第四節 Macrolides、mucolytic agents及statins 與急性惡化風險的相關性 97
第五節 研究限制 105
第六章 結論與建議 108
參考文獻 109

圖目錄
圖1-1-1 Cole 惡性循環假說 20
圖3-2-1 資料處理流程 53
圖4-2-1 Kaplan-Meier急性惡化累積風險曲線 68
圖4-2-2 Kaplan-Meier存活機率曲線 75

表目錄
表1-1-1 慢性阻塞性肺病患者氣流受阻的嚴重度分類 9
表2-1-1 歷年慢性阻塞性肺病合併支氣管擴張症與急性惡化相關研究 34
表2-1-2 歷年慢性阻塞性肺病合併支氣管擴張症與死亡相關研究 35
表3-2-1 資料檔案名稱與擷取變項 39
表3-2-2 胸部X光診療項目代碼 42
表3-2-3 電腦斷層掃描診療項目代碼 42
表3-2-4 肺炎相關抗生素及系統性類固醇 47
表3-2-5 研究變項之操作型定義 50
表4-1-1 病人基本特性分佈 60
表4-1-2 慢性阻塞性肺病有無合併支氣管擴張症患者之急性惡化率 64
表4-1-3 慢性阻塞性肺病有無合併支氣管擴張症患者之急性惡化用藥 66
表4-2-1 支氣管擴張症及其他控制變項與中至重度急性惡化風險的相關性 70
表4-2-2 支氣管擴張症及其他控制變項與重度急性惡化風險的相關性 72
表4-2-3 支氣管擴張症及其他控制變項與死亡風險的相關性 76
表4-3-1 支氣管擴張劑與急性惡化風險的相關性 79
表4-4-1 Macrolides、mucolytic agents及statins與急性惡化風險的相關性 82

Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146:545-55.
Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health. 2015;5:020415.
Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122.
Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-98.
Almagro P, Salvado M, Garcia-Vidal C, et al. Pseudomonas aeruginosa and mortality after hospital admission for chronic obstructive pulmonary disease. Respiration. 2012;84:36-43.
Altenburg J, de Graaff CS, Stienstra Y, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309:1251-9.
Amalakuhan B, Maselli DJ, and Martinez-Garcia MA. Update in bronchiectasis 2014. Am J Respir Crit Care Med. 2015;192:1155-61.
Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA. 1994;272:1497-505.
Barker AF, O'Donnell AE, Flume P, et al. Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials. Lancet Respir Med. 2014;2:738-49.
Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov. 2013;12:543-59.
Baron RM, and Bartlett JG (2012). Chapter 258. Bronchiectasis and Lung Abscess. Harrison's Principles of Internal Medicine, 18e. Longo DL, Fauci AS, Kasper DL, et al. New York, NY, The McGraw-Hill Companies.
Barr RG, Rowe BH, and Camargo CA, Jr. Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomised trials. BMJ. 2003;327:643.
Belmonte KE. Cholinergic pathways in the lungs and anticholinergic therapy for chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2:297-304; discussion 311-2.
Bhowmik A, Seemungal TA, Sapsford RJ, et al. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55:114-20.
Bilton D, Tino G, Barker AF, et al. Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial. Thorax. 2014;69:1073-9.
Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-89.
Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-94.
Cazzola M, and Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23:257-67.
Celli BR, and Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 2007;29:1224-38.
Celli BR, and MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-46.
Chalmers JD, Aliberti S, and Blasi F. Management of bronchiectasis in adults. Eur Respir J. 2015;45:1446-62.
Chan TC, Chiang PH, Su MD, et al. Geographic disparity in chronic obstructive pulmonary disease (COPD) mortality rates among the Taiwan population. PLoS One. 2014;9:e98170.
Cosio BG, Shafiek H, Iglesias A, et al. Oral low-dose theophylline on top of inhaled fluticasone-salmeterol does not reduce exacerbations in patients with severe COPD: a pilot clinical trial. Chest. 2016;150:123-30.
Crim C, Dransfield MT, Bourbeau J, et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc. 2015;12:27-34.
Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014;370:2201-10.
de Marco R, Accordini S, Marcon A, et al. Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults. Am J Respir Crit Care Med. 2011;183:891-7.
Decramer M, Rutten-van Molken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365:1552-60.
Decramer ML, Chapman KR, Dahl R, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med. 2013;1:524-33.
Dicpinigaitis PV, Spinner L, Santhyadka G, et al. Effect of tiotropium on cough reflex sensitivity in acute viral cough. Lung. 2008;186:369-74.
Du Q, Jin J, Liu X, et al. Bronchiectasis as a comorbidity of chronic obstructive pulmonary disease: a systematic review and meta-analysis. PloS One. 2016;11:e0150532.
Eisner MD, Anthonisen N, Coultas D, et al. An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182:693-718.
Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374:695-703.
Falk JA, Kadiev S, Criner GJ, et al. Cardiac disease in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5:543-8.
Fexer J, Donnachie E, Schneider A, et al. The effects of theophylline on hospital admissions and exacerbations in COPD patients: audit data from the Bavarian disease management program. Dtsch Arztebl Int. 2014;111:293-300.
Gatheral T, Kumar N, Sansom B, et al. COPD-related bronchiectasis; independent impact on disease course and outcomes. COPD. 2014;11:605-14.
Gauderman WJ, Avol E, Gilliland F, et al. The effect of air pollution on lung development from 10 to 18 years of age. N Engl J Med. 2004;351:1057-67.
Geake JB, Dabscheck EJ, Wood-Baker R, et al. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta(2)-agonists or placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;1:Cd010139.
Goeminne PC, Nawrot TS, Ruttens D, et al. Mortality in non-cystic fibrosis bronchiectasis: a prospective cohort analysis. Respir Med. 2014;108:287-96.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (updated 2006). Available from:
http://www.who.int/respiratory/copd/GOLD_WR_06.pdf. Accessed July 7, 2017. 2006.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (updated 2017). Available from: http://www.goldcopd.org/. Accessed January 7, 2017. 2017.
Gross N, Tashkin D, Miller R, et al. Inhalation by nebulization of albuterol-ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group. Respiration. 1998;65:354-62.
Guarascio AJ, Ray SM, Finch CK, et al. The clinical and economic burden of chronic obstructive pulmonary disease in the USA. Clinicoecon Outcomes Res. 2013;5:235-45.
Gursel G. Does coexistence with bronchiectasis influence intensive care unit outcome in patients with chronic obstructive pulmonary disease? Heart Lung. 2006;35:58-65.
Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523-32.
Han MK. Clinical correlations of computed tomography imaging in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013;10 Suppl:S131-7.
Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010;182:598-604.
Han MK, Muellerova H, Curran-Everett D, et al. GOLD 2011 disease severity classification in COPDGene: a prospective cohort study. Lancet Respir Med. 2013;1:43-50.
Hasani A, Toms N, Agnew JE, et al. The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD. Chest. 2004;125:1726-34.
Haworth CS, Foweraker JE, Wilkinson P, et al. Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med. 2014;189:975-82.
Herath SC, and Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2013:Cd009764.
Holme J, Tomlinson JW, Stockley RA, et al. Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids. Eur Respir J. 2008;32:1047-52.
Howard ML, and Vincent AH. Statin effects on exacerbation rates, mortality, and inflammatory markers in patients with chronic obstructive pulmonary disease: a review of prospective studies. Pharmacotherapy. 2016;36:536-47.
Hoyert DL, and Xu J. Deaths: preliminary data for 2011. Natl Vital Stat Rep. 2012;61:1-51.
Hunninghake GM, Cho MH, Tesfaigzi Y, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med. 2009;361:2599-608.
Hurst JR, Donaldson GC, Quint JK, et al. Temporal clustering of exacerbations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:369-74.
Hurst JR, Elborn JS, and Soyza AD. COPD–bronchiectasis overlap syndrome. Eur Respir J. 2015;45:310-3.
Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128-38.
Hwang S-L, Lin Y-C, Guo S-E, et al. Prevalence of chronic obstructive pulmonary disease in southwestern taiwan: a population-based study. Int J Respir Pulm Med. 2016;3:048.
Ip MS, So SY, Lam WK, et al. High prevalence of asthma in patients with bronchiectasis in Hong Kong. Eur Respir J. 1992;5:418-23.
Jones PW. Health status and the spiral of decline. COPD. 2009;6:59-63.
Jung KS, Park HY, Park SY, et al. Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. Respir Med. 2012;106:382-9.
Kapur N, Bell S, Kolbe J, et al. Inhaled steroids for bronchiectasis. Cochrane Database Syst Rev. 2009:Cd000996.
Karner C, Chong J, and Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014:Cd009285.
Kellett F, and Robert NM. Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis. Respir Med. 2011;105:1831-5.
Kempsford R, Norris V, and Siederer S. Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD. Pulm Pharmacol Ther. 2013;26:256-64.
Kew KM, Mavergames C, and Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013:Cd010177.
Kim V, Han MK, Vance GB, et al. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest. 2011;140:626-33.
Koch A, Pizzichini E, Hamilton A, et al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat(R) versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014;9:697-714.
Kohansal R, Martinez-Camblor P, Agusti A, et al. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med. 2009;180:3-10.
Lao X, Liu J, Tang X, et al. Bronchiectasis in COPD: A new phenotype of COPD with particular attention. J Pulm Respir Med. 2014;5:226.
Lee AL, Burge AT, and Holland AE. Airway clearance techniques for bronchiectasis. Cochrane Database Syst Rev. 2015:Cd008351.
Lee JH, Kim HJ, and Kim YH. The effectiveness of anti-leukotriene agents in patients with COPD: a systemic review and meta-analysis. Lung. 2015;193:477-86.
Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309:2223-31.
Loebinger MR, Wells AU, Hansell DM, et al. Mortality in bronchiectasis: a long-term study assessing the factors influencing survival. Eur Respir J. 2009;34:843-9.
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095-128.
Lujan M, Gallardo X, Amengual MJ, et al. Prevalence of bronchiectasis in asthma according to oral steroid requirement: influence of immunoglobulin levels. Biomed Res Int. 2013;2013:109219.
MacNee W. Pathology, pathogenesis, and pathophysiology. BMJ. 2006;332:1202-4.
Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: Efficacy and safety of QVA149 (indacaterol/glycopyrrolate) versus its monocomponents and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192:1068-79.
Mandal P, Chalmers JD, Graham C, et al. Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med. 2014;2:455-63.
Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32:962-9.
Martinez-Garcia MA, de la Rosa Carrillo D, Soler-Cataluna JJ, et al. Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187:823-31.
Martinez-Garcia MA, and Miravitlles M. Bronchiectasis in COPD patients: more than a comorbidity? Int J Chron Obstruct Pulmon Dis. 2017;12:1401-11.
Martinez-Garcia MA, Soler-Cataluna JJ, Catalan-Serra P, et al. Clinical efficacy and safety of budesonide-formoterol in non-cystic fibrosis bronchiectasis. Chest. 2012;141:461-8.
Martinez-Garcia MA, Soler-Cataluna JJ, Donat Sanz Y, et al. Factors associated with bronchiectasis in patients with COPD. Chest. 2011;140:1130-7.
Martinez FJ, Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015;385:857-66.
Martinez FJ, Curtis JL, and Albert R. Role of macrolide therapy in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008;3:331-50.
Mathers CD, and Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3:e442.
McGeachie MJ, Yates KP, Zhou X, et al. Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med. 2016;374:1842-52.
McShane PJ, Naureckas ET, Tino G, et al. Non–cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2013;188:647-56.
Mercado N, Ito K, and Barnes PJ. Accelerated ageing of the lung in COPD: new concepts. Thorax. 2015;70:482-9.
Meyer T, Reitmeir P, Brand P, et al. Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD. Respir Med. 2011;105:900-6.
Moxham J. Aminophylline and the respiratory muscles: an alternative view. Clin Chest Med. 1988;9:325-36.
Murray MP, Turnbull K, Macquarrie S, et al. Assessing response to treatment of exacerbations of bronchiectasis in adults. Eur Respir J. 2009;33:312-8.
Nair GB, and Ilowite JS. Pharmacologic agents for mucus clearance in bronchiectasis. Clin Chest Med. 2012;33:363-70.
Nannini LJ, Lasserson TJ, and Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012:Cd006829.
Nannini LJ, Poole P, Milan SJ, et al. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013:Cd006826.
Navaratnam V, Millett ER, Hurst JR, et al. Bronchiectasis and the risk of cardiovascular disease: a population-based study. Thorax. 2017;72:161-6.
Ni Y, Shi G, Yu Y, et al. Clinical characteristics of patients with chronic obstructive pulmonary disease with comorbid bronchiectasis: a systemic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015:1465.
Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340:1941-7.
Niewoehner DE, Lokhnygina Y, Rice K, et al. Risk indexes for exacerbations and hospitalizations due to COPD. Chest. 2007;131:20-8.
Nishimura K, Izumi T, Tsukino M, et al. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest. 2002;121:1434-40.
Nouira S, Marghli S, Belghith M, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet. 2001;358:2020-5.
Novosad SA, and Barker AF. Chronic obstructive pulmonary disease and bronchiectasis. Curr Opin Pulm Med. 2013;19:133-9.
O'Brien C, Guest PJ, Hill SL, et al. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax. 2000;55:635-42.
Pasteur MC, Bilton D, and Hill AT. British thoracic society guideline for non-CF bronchiectasis. Thorax. 2010;65 Suppl 1:i1-58.
Patel IS, Seemungal TA, Wilks M, et al. Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Thorax. 2002;57:759-64.
Patel IS, Vlahos I, Wilkinson TM, et al. Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170:400-7.
Paulin LM, Diette GB, Blanc PD, et al. Occupational exposures are associated with worse morbidity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:557-65.
Poole P, Chong J, and Cates CJ. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015:Cd001287.
Poole PJ. Role of mucolytics in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2006;1:123-8.
Qureshi H, Sharafkhaneh A, and Hanania NA. Chronic obstructive pulmonary disease exacerbations: latest evidence and clinical implications. Ther Adv Chronic Dis. 2014;5:212-27.
Ram FS, Jones PW, Castro AA, et al. Oral theophylline for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2002:Cd003902.
Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006:Cd004403.
Rice KL, Rubins JB, Lebahn F, et al. Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial. Am J Respir Crit Care Med. 2000;162:174-8.
Riise GC, Larsson S, Larsson P, et al. The intrabronchial microbial flora in chronic bronchitis patients: a target for N-acetylcysteine therapy? Eur Respir J. 1994;7:94-101.
Sanguinetti CM. N-acetylcysteine in COPD: why, how, and when? Multidiscip Respir Med. 2016;11:8.
Seemungal TA, Wilkinson TM, Hurst JR, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178:1139-47.
Seitz AE, Olivier KN, Adjemian J, et al. Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007. Chest. 2012;142:432-9.
Serisier DJ, Bilton D, De Soyza A, et al. Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. Thorax. 2013;68:812-7.
Serisier DJ, Martin ML, McGuckin MA, et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA. 2013;309:1260-7.
Shi ZL, Peng H, Hu XW, et al. Effectiveness and safety of macrolides in bronchiectasis patients: a meta-analysis and systematic review. Pulm Pharmacol Ther. 2014;28:171-8.
Sibila O, Suarez-Cuartin G, Rodrigo-Troyano A, et al. Secreted mucins and airway bacterial colonization in non-CF bronchiectasis. Respirology. 2015;20:1082-8.
Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016;388:963-73.
Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-31.
Stoller JK, and Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365:2225-36.
Su VY, Chang YS, Hu YW, et al. Carvedilol, bisoprolol, and metoprolol use in patients with coexistent heart failure and chronic obstructive pulmonary disease. Medicine (Baltimore). 2016;95:e2427.
Tager IB, Ngo L, and Hanrahan JP. Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life. Am J Respir Crit Care Med. 1995;152:977-83.
Tam A, Churg A, Wright JL, et al. Sex differences in airway remodeling in a mouse model of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2016;193:825-34.
Tashkin DP, Pearle J, Iezzoni D, et al. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD. 2009;6:17-25.
Tsang KW, Ho PL, Lam WK, et al. Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis. Am J Respir Crit Care Med. 1998;158:723-7.
Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013;144:106-18.
Tumkaya M, Atis S, Ozge C, et al. Relationship between airway colonization, inflammation and exacerbation frequency in COPD. Respiratory Medicine. 2007;101:729-37.
Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2:361-8.
van Overveld FJ, Vermeire PA, and De Backer WA. Induced sputum of patients with chronic obstructive pulmonary disease (COPD) contains adhesion-promoting, therapy-sensitive factors. Inflamm Res. 2000;49:8-13.
Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093-103.
Walters JA, Tan DJ, White CJ, et al. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014:Cd001288.
Wang M-T, Lo Y-W, Tsai C-L, et al. Statin use and risk of COPD exacerbation requiring hospitalization. Am J Med. 2013;126:598-606.e2.
Wang Y, Ghoshal AG, Bin Abdul Muttalif AR, et al. Quality of life and economic burden of respiratory disease in Asia-Pacific-Asia-Pacific burden of respiratory diseases study. Value Health Reg Issues. 2016;9:72-7.
Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016;374:2222-34.
Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013;1:199-209.
Wedzicha JA, and Hurst JR. Structural and functional co-conspirators in chronic obstructive pulmonary disease exacerbations. Proc Am Thorac Soc. 2007;4:602-5.
Wedzicha JA, and Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-96.
Weycker D, Edelsberg J, Oster G, et al. Prevalence and economic burden of bronchiectasis. Clin Pulm Med. 2005;12:205-9.
Whitters D, and Stockley RA. Bronchiectasis in older patients with chronic obstructive pulmonary disease. Drugs Aging. 2013;30:215-25.
Wilson R, Welte T, Polverino E, et al. Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J. 2013;41:1107-15.
Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380:660-7.
Yang IA, Clarke MS, Sim EH, et al. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012:Cd002991.
Yu C-J, Cheng S-L, Chan M-C, et al. COPD in Taiwan: a national epidemiology survey. Int J Chron Obstruct Pulmon Dis. 2015;10:2459-67.
Zacarias EC, Castro AA, and Cendon S. Effect of theophylline associated with short-acting or long-acting inhaled beta2-agonists in patients with stable chronic obstructive pulmonary disease: a systematic review. J Bras Pneumol. 2007;33:152-60.
Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology. 2006;11:603-10.
Zhou Y, Zou Y, Li X, et al. Lung function and incidence of chronic obstructive pulmonary disease after improved cooking fuels and kitchen ventilation: a 9-year prospective cohort study. PLoS Med. 2014;11:e1001621.
洪錦墩、李淑芬、李明輝 等人。台灣支氣管擴張症相關疾病之住院趨勢分析。醫學與健康期刊，2013;第2卷:43-52.