自从2001年慢性阻塞性肺疾病全球倡议（GOLD）颁布第1版慢性阻塞性肺疾病诊断、处理和预防全球策略（简称慢阻肺全球策略），至今已整整16年了，16年中慢性阻塞性肺疾病（慢阻肺，COPD）的临床研究取得了相当大的进展。

Abstract BACKGROUND: The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) has been the subject of much controversy. Major international guidelines recommend selective use of ICS. Recently published meta-analyses have reported conflicting findings on the effects of inhaled steroid therapy in COPD. OBJECTIVES: The objective of the review is to determine the efficacy of regular use of inhaled corticosteroids in patients with stable COPD. SEARCH STRATEGY: A pre-defined search strategy was used to search the Cochrane Airways Group specialised register for relevant literature. Searches are current as of October 2006. SELECTION CRITERIA: We selected randomised trials comparing any dose of any type of inhaled steroid with a placebo control in patients with COPD. Acute bronchodilator reversibility to short term beta2-agonists and bronchial hyperresponsiveness were not exclusion criteria. The a priori primary outcome was change in lung function. Data on mortality, exacerbations, quality of life and symptoms, rescue bronchodilator use, exercise capacity, biomarkers and safety were also analysed. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Forty-seven primary studies with 13,139 participants met the inclusion criteria. Medium term use of ICS (> two months and up to six months) resulted in a small improvement in FEV1 in some studies. Long term use of ICS (> six months) did not significantly reduce the rate of decline in FEV1 in COPD patients (weighted mean difference (WMD) 5.80 ml/year with ICS over placebo, 95% CI -0.28 to 11.88, 2333 participants). There was no statistically significant effect on mortality in COPD patients (OR 0.98, 95% CI 0.83 to 1.16, 8390 participants). Long term use of ICS reduced the mean rate of exacerbations in those studies where pooling of data was possible (WMD -0.26 exacerbations per patient per year, 95% CI -0.37 to -0.14, 2586 participants). ICS slowed the rate of decline in quality of life, as measured by the St George's Respiratory Questionnaire (WMD -1.22 units/year, 95% CI -1.83 to -0.60, 2507 participants). Response to ICS was not predicted by oral steroid response, bronchodilator reversibility or bronchial hyper-responsiveness in COPD patients. There was an increased risk of oropharyngeal candidiasis (OR 2.49, 95% CI 1.78 to 3.49, 4380 participants) and hoarseness. The few long term studies that measured bone effects generally showed no major effect on fractures and bone mineral density over 3 years. AUTHORS' CONCLUSIONS: Patients and clinicians should balance the potential benefits of inhaled steroids in COPD (reduced rate of exacerbations, reduced rate of decline in quality of life), against the known increase in local side effects (oropharyngeal candidiasis and hoarseness). The risk of long term adverse effects is unknown.

Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β2 agonist is more protective than a once-daily longacting β2 agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone. We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV1 of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952). 1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 [95% CI 0·7–1·0]). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group. Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk. GlaxoSmithKline.

Abstract RATIONALE: Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date. OBJECTIVES: To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history. METHODS: Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 0204g or VI 25 0204g combined with 50, 100, or 200 0204g FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation. MEASUREMENTS AND MAIN RESULTS: Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 0204g FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index <25 kg/m(2), and severe airflow limitation. CONCLUSIONS: Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigator-defined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management. Clinical trial registered with www.clinicaltrials.gov ( NCT01009463 [HZC102871]; NCT01017952 [HZC102970]).

ClinicalTrials.gov Identifier: NTC00268216

Background The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD.<br/>Methods MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (>= 24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose-response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I(2) statistic.<br/>Results Sixteen RCTs (14 fluticasone, 2 budesonide) with 17 513 participants, and seven observational studies (n = 69 000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p = 0.04; I(2) = 0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p < 0.001; I(2) = 37%), with each 500 mu g increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p < 0.001).<br/>Conclusion Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.

Abstract BACKGROUND: Chronic respiratory disease and inhaled corticosteroid (ICS) therapy for chronic obstructive pulmonary disease (COPD) increase the risk of pneumonia. Few data are available on the association of these risk factors with non-tuberculous mycobacterial (NTM) pulmonary disease. METHODS: This study examined chronic respiratory diseases and ICS use as risk factors in a population-based case-control study encompassing all adults in Denmark with microbiologically confirmed NTM pulmonary disease between 1997 and 2008. The study included 10 matched population controls per case. Conditional logistic regression was used to compute adjusted ORs for NTM pulmonary disease with regard to chronic respiratory disease history. RESULTS: Overall, chronic respiratory disease was associated with a 16.5-fold (95% CI 12.2 to 22.2) increased risk of NTM pulmonary disease. The adjusted OR for NTM disease was 15.7 (95% CI 11.4 to 21.5) for COPD, 7.8 (95% CI 5.2 to 11.6) for asthma, 9.8 (95% CI 2.03 to 52.8) for pneumoconiosis, 187.5 (95% CI 24.8 to 1417.4) for bronchiectasis, and 178.3 (95% CI 55.4 to 574.3) for tuberculosis history. ORs were 29.1 (95% CI 13.3 to 63.8) for patients with COPD on current ICS therapy and 7.6 (95% CI 3.4 to 16.8) for patients with COPD who had never received ICS therapy. Among patients with COPD, ORs increased according to ICS dose, from 28.1 for low-dose intake to 47.5 for high-dose intake (more than 800 渭g/day). The OR was higher for fluticasone than for budesonide. CONCLUSION: Chronic respiratory disease, particularly COPD treated with ICS therapy, is a strong risk factor for NTM pulmonary disease.

The use of inhaled corticosteroids (ICSs) is associated with an increased risk of pneumonia in patients with COPD. However, the risks of other respiratory infections, such as TB and influenza, remain unclear. Through a comprehensive literature search of MEDLINE, EMBASE, CINAHL, Cochrane Library, andClinicalTrials.govfrom inception to July 2013, we identified randomized controlled trials of ICS therapy lasting at least 6 months. We conducted meta-analyses by the Peto, Mantel-Haenszel, and Bayesian approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of TB and influenza. Twenty-five trials (22, 898 subjects) for TB and 26 trials (23, 616 subjects) for influenza were included. Compared with non-ICS treatment, ICS treatment was associated with a significantly higher risk of TB (Peto OR, 2.29; 95% CI, 1.04-5.03) but not influenza (Peto OR, 1.24; 95% CI, 0.94-1.63). Results were similar with each meta-analytic approach. Furthermore, the number needed to harm to cause one additional TB event was lower for patients with COPD treated with ICSs in endemic areas than for those in nonendemic areas (909 vs 1, 667, respectively). This study raises safety concerns about the risk of TB and influenza associated with ICS use in patients with COPD, which deserve further investigation.

We evaluated the effect of dual, longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease (COPD). In this parallel-group study, 2224 patients (aged ≥40 years, Global Initiative for Chronic Obstructive Lung Disease stages III–IV, and one or more moderate COPD exacerbation in the past year) were randomly assigned (1:1:1; via interactive voice response or web system; stratified for smoking status) to once-daily QVA149 (fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg), glycopyrronium 50 μg, or tiotropium 18 μg for 64 weeks. Assignment to QVA149 and glycopyrronium was double-blind; tiotropium was open-label. Efficacy was assessed in all patients randomly assigned to treatment groups who received at least one dose of study drug; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group. The primary objective was to show superiority of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations (defined by worsening symptoms and categorised by treatment requirements) during treatment. This completed trial is registered at ClinicalTrials.gov, NCT01120691. Between April 27, 2010, and July 11, 2012, 741 patients were randomly assigned to receive QVA149, 741 to receive glycopyrronium, and 742 to receive tiotropium (729, 739, and 737 patients, respectively, analysed for efficacy). QVA149 significantly reduced the rate of moderate to severe exacerbations versus glycopyrronium by 12% (annualised rate of exacerbations 0·84 [95% CI 0·75–0·94] vs 0·95 [0·85–1·06]; rate ratio 0·88, 95% CI 0·77–0·99, p=0·038). Adverse events (including exacerbations) were reported for 678 (93%) of 729 patients on QVA149, 694 (94%) of 740 on glycopyrronium, and 686 (93%) of 737 on tiotropium. Incidence of serious adverse events was similar between groups (167 [23%] patients on QVA149, 179 [24%] on glycopyrronium, and 165 [22%] on tiotropium); COPD worsening was the most frequent serious adverse event (107 [15%] patients on QVA149, 116 [16%] on glycopyrronium, 87 [12%] on tiotropium). The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium, with concomitant improvements in lung function and health status. These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD. Novartis Pharma AG.

Abstract Background Long-acting beta-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. However, they have only been available until recently via separate administration. They have been developed in order to facilitate adherence to medication regimens, and to improve efficacy. Objectives To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations in the treatment of adults with chronic obstructive pulmonary disease. Search strategy We searched the Cochrane Airways Group chronic obstructive pulmonary disease (COPD) trials register (March 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), LILACS (all years to March 2003) and reference lists of articles. We also contacted manufacturers and researchers in the field. Selection criteria Studies were included if they were randomised, with adequate blinding procedures in place. Studies could compare a combined inhaled corticosteroids and long-acting beta-agonist preparation with either component preparation or placebo. Studies comparing different members of each class of combined therapies were included Data collection and analysis Two reviewers independently assessed trial quality and extracted data. Main results Four randomised trials with 2986 participants were included. Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were studied in the trials. No meta-analysis on clinical outcomes was possible due to different outcome assessment across studies. All studies demonstrated a reduction in exacerbation rates versus placebo. Budesonide/formoterol was more effective than formoterol in reducing exacerbations in one study from 1.84 to 1.42 exacerbations per year. Fluticasone/salmeterol did not significantly reduce exacerbations compared with either of its component treatments. Fluticasone/salmeterol led to better quality of life compared with placebo (two studies), although there were conflicting results when compared with inhaled corticosteroid alone (two studies). There was no significant difference between fluticasone/salmeterol and long-acting beta-agonist (two studies). Budesonide/formoterol led to statistically significant differences in quality of life compared with placebo, but not when compared with component inhaled corticosteroid or beta-agonist (one study). Reviewers' conclusions For the primary outcome of exacerbations, budesonide/formoterol had a modest advantage over a component medication, formoterol, in a single trial, but fluticasone/salmeterol did not result in a significant reduction in exacerbations compared to either of its components. The combination of steroids and long-acting beta-agonist in one inhaler was effective in improving symptoms compared with placebo and on certain clinical outcomes compared with one of the individual components alone. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, including the assessment of the comparative effects with separate administration of the two drugs in double-dummy trials.

Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease (COPD). In two 12-week, double-blind, parallel-group studies, patients with COPD were randomized 1:1:1 to once-daily umeclidinium (UMEC; 62.5 0204g and 125 0204g) or placebo (PBO), added to twice-daily fluticasone propionate/salmeterol (FP/SAL; 250/50 0204g). In both studies, the primary efficacy measure was trough forced expiratory volume in 1 second (FEV1) at Day 85. Secondary endpoints were weighted-mean (WM) FEV1 over 00900096 hours post-dose (Day 84) and rescue albuterol use. Health-related quality of life outcomes (St. George''s Respiratory Questionnaire [SGRQ] and COPD assessment test [CAT]) were also examined. Safety was assessed throughout. Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV1 (Day 85: 0.1270900090.148 L) versus PBO+FP/SAL. Similarly, both UMEC+FP/SAL doses provided statistically-significant improvements in 00900096 hours post-dose WM FEV1versus PBO+FP/SAL (Day 84: 0.1440900090.165 L). Rescue use over Weeks 109000912 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL (Study 1, 0.3 puffs/day [both doses]; Study 2, 0.5 puffs/day [UMEC 125+FP/SAL]). Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL (except for Day 84 Study 2). In Study 1, no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL; however, in Study 2, statistically significant improvements were observed with UMEC 62.5+FP/SAL (Day 28) and UMEC 125+FP/SAL (Days 28 and 84) versus PBO+FP/SAL. The incidence of on-treatment adverse events across all treatment groups was 3709000941% in Study 1 and 3609000938% in Study 2. Overall, these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD.

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society () and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

Abstract BACKGROUND: Inadequate technique reduces the effects of inhalation medication. Errors in inhalation technique have been reported to range up to 85%. Not only various patients' characteristics but also the device has an effect on correct inhalation technique. The purpose of this study was to determine the effect of patients' characteristics and type of inhaler device on inhalation technique in patient with asthma or chronic obstructive pulmonary disease (COPD). METHODS: A validated scoring method was used that consisted of triple viewing of video-recorded inhalations, using device-specific checklists. The following patient characteristics were investigated: gender, age, education level, diagnosis, treatment by a pulmonary physician, previously received inhalation instruction, exacerbation frequency, knowledge, self-management competence, pulmonary function, and use of multiple inhaler devices. Chi-square statistics were used for univariate associations between potential determinants and correctness of inhalation technique. Relevant determinants were entered into a multivariate logistic regression model. Moreover, inhalation technique errors were examined for six inhaler devices: three prefilled dry powder inhalers, one single-dose dry powder inhaler, a pressurized metered-dose inhaler (pMDI) and a pMDI with a spacer. RESULTS: Overall, 40% of the patients made at least one essential mistake in their inhalation technique. Patients who never received inhalation instruction and patients who used more than one inhaler device made significantly more errors (odds ratio both 2.2). Comparison between devices showed that a correct inhalation technique most likely occurred with the use of prefilled dry powder devices. CONCLUSION: Incorrect inhalation technique is common among asthma and COPD patients in a pulmonary outpatient clinic. Our study suggests that the use of prefilled dry powder inhalers as well as inhalation instruction increases correct inhalation technique. Simultaneous use of different types of inhalation devices has to be discouraged.

目的:探究铝碳酸镁联合质子泵抑制剂(PPI)治疗慢性阻塞性肺疾病(COPD)合并咽喉反流的疗效及对慢性阻塞性肺疾病急性加重(AECOPD)的预防作用.方法:选取2015年6月到2017年6月于本院就诊的98例COPD合并咽喉反流患者,随机数字表法分为研究组和对照组,各49例.两组患者均给予常规COPD药物治疗,对照组患者给予PPI治疗,研究组在此基础上给予铝碳酸镁联合治疗,院外随访12个月.比较两组患者临床疗效、治疗前后咽喉部24 h连续pH监测情况、肺功能和咽喉反流指标,应用Kaplan-Meier法绘制生存曲线,分析两组患者AECOPD发作和死亡风险间的差异.结果:两组患者临床疗效存在差异(Z=-1.976,P=0.048),且研究组治疗有效率显著高于对照组(97.96％ 和79.59％,χ2=8.295,P=0.004);治疗后两组患者酸反流次数、Ryan指数和酸反流总时间均显著减少,且研究组显著低于对照组,差异具有统计学意义(P<0.05);治疗后,两组患者第1秒用力呼气容积占预计值百分比(FEV1％)和第1秒用力呼气容积/用力肺活量(FEV1/FVC)均显著升高,自我评估测试(CAT)、反流症状指数评分量表(RSI)和反流体征评分量表(RFS)评分均显著降低,且研究组FEV1％和FEV1/FVC均显著高于对照组,CAT、RSI和RFS评分均显著低于对照组,差异具有统计学意义(P<0.05);对照组和研究组在出院后12个月内的急性发作率分别为69.39％(34/49)和46.94％(23/49),研究组的急性发作风险显著低于对照组(HR=0.513,95％CI[0.318,0.904],P=0.015);对照组和研究组在出院后12个月内分别有2例和1例死亡病例,研究组和对照组的死亡风险间无明显差异(HR=0.489,95％CI[0.050,4.709],P=0.551).结论:铝碳酸镁联合PPI治疗COPD合并咽喉反流能显著提高临床疗效,有效改善患者肺功能和咽喉反流症状,明显降低COPD急性发作发生风险,值得临床推广.