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In patients with COPD, acute exacerbation (AE) is not only an important determinant of prognosis, but also an important factor in choosing therapeutic agents. In this study, we evaluated the usefulness of COPD subtypes identified through cluster analysis to predict the first AE. Among COPD patients in the Korea COPD Subgroup Study (KOCOSS) cohort, 1,195 who had follow-up data for AE were included in our study. We selected seven variables for cluster analysis - age, body mass index, smoking status, history of asthma, COPD assessment test (CAT) score, post-bronchodilator (BD) FEV % predicted, and diffusing capacity of carbon monoxide % predicted. K-means clustering identified four clusters for COPD that we named putative asthma-COPD overlap (ACO), mild COPD, moderate COPD, and severe COPD subtypes. The ACO group (n=196) showed the second-best post-BD FEV (75.5% vs 80.9% [mild COPD, n=313] vs 52.4% [moderate COPD, n=345] vs 46.7% [severe COPD, n=341] predicted), the longest 6-min walking distance (424 m vs 405 m vs 389  m vs 365 m), and the lowest CAT score (12.2 vs 13.7 vs 15.6 vs 17.5) among the four groups. ACO group had greater risk for first AE compared to the mild COPD group (HR, 1.683; 95% CI, 1.175-2.410). The moderate COPD and severe COPD group HR values were 1.587 (95% CI, 1.145-2.200) and 1.664 (95% CI, 1.203-2.302), respectively. In addition, St. George's Respiratory Questionnaire score (HR: 1.019; 95% CI, 1.014-1.024) and gastroesophageal reflux disease were independent factors associated with the first AE (HR: 1.535; 95% CI, 1.116-2.112). Our cluster analysis revealed an exacerbator subtype of COPD independent of FEV . Since these patients are susceptible to AE, a more aggressive treatment strategy is needed in these patients.

Inadequacy of antioxidant nuclear factor-E2-related factor 2 (Nrf2) and endoplasmic reticulum stress-mediated unfolded protein response has been implicated in severe chronic obstructive pulmonary disease (COPD) and cigarette smoking-induced emphysema. As evidence suggests that the ability to upregulate Nrf2 expression may influence the progression of COPD and no data exist up to now in ex-smokers with mild-moderate COPD, this study was first aimed to evaluate Nrf2 and unfolded protein response expression in peripheral blood mononuclear cells (PBMC) of mild-moderate ex-smokers with COPD compared to smoking habit-matched non-COPD subjects. Then, we tested whether oxidative stress persists after cigarette smoking cessation and whether the concentrations of oxidized phospholipids (oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine [oxPAPC]) in the PBMC of the same subjects may have a causative role in determining the upregulation of Nrf2. The expression (mRNA and protein) of Nrf2 and of its related gene heme oxygenase-1 was significantly increased in COPD group without differences in the unfolded protein response. Plasma malondialdehyde, the circulating marker of oxidative stress, and oxPAPC in PBMC were significantly higher in COPD than in non-COPD subjects. The fact that the expression of p47phox, a subunit of NADPH oxidase, was increased in PBMC of COPD patients and that it was directly correlated with oxPAPC may indicate that oxPAPC may be one of the determinants of oxidative stress-induced Nrf2 upregulation. Finally, we also demonstrated that lung function inversely correlated with plasma malondialdehyde and with Nrf2 and heme oxygenase-1 mRNA expression in all subjects. Our results indicate that mild-moderate ex-smokers with COPD may be able to counteract oxidative stress by increasing the expression of Nrf2/antioxidant-response elements. Because Nrf2 failure significantly contributes to the development of COPD, our findings suggest that the possibility to prevent Nrf2 reduction may open a new scenario in helping to prevent the oxidative stress-associated lung function decline.

To describe the self-management (SM) behavior among persons with mild-to-moderate chronic obstructive pulmonary disease (COPD), and it examines the correlation between COPD knowledge, self-efficacy, perceived social support, and SM behavior among persons with mild-to-moderate COPD in Wenzhou, China.A simple random sampling technique was used to recruit 121 persons with mild-to-moderate COPD who visited the respiratory outpatient department of the First Affiliated Hospital of Wenzhou Medical University in Wenzhou, China. Research instruments include a demographic data questionnaire, COPD SM scale, COPD knowledge questionnaire, 6-item chronic disease self-efficacy scale, and perceived social support scale. Descriptive statistics and Pearson’s Correlation were used for data analysis.The findings show that the mean score of COPD SM scale was 2.70 (SD = 0.45). The Pearson correlation analysis revealed that the COPD knowledge (r = 0.47, P < 0.001), self-efficacy (r = 0.28, P = 0.001), and perceived social support (r = 0.48, P < 0.001) were positively correlated to the COPD SM behavior among persons with mild-to-moderate COPD in Wenzhou, China.The findings indicate that disease knowledge, self-efficacy, and perceived social support were related to SM behavior in persons with mild-to-moderate COPD, which provides a theoretical basis for developing SM interventions for persons with mild-to-moderate COPD and improving this population’s SM behavior.

Anna Maria Fratta Pasini,1 Marcello Ferrari,2 Chiara Stranieri,1 Paola Vallerio,1 Chiara Mozzini,1 Ulisse Garbin,1 Giorgia Zambon,1 Luciano Cominacini1 1Department of Medicine, Section of Internal Medicine, 2Department of Medicine, Unit of Respiratory Diseases, University of Verona, Verona,Italy Abstract: Inadequacy of antioxidant nuclear factor-E2-related factor 2 (Nrf2) and endoplasmic reticulum stress-mediated unfolded protein response has been implicated in severe chronic obstructive pulmonary disease (COPD) and cigarette smoking-induced emphysema. As evidence suggests that the ability to upregulate Nrf2 expression may influence the progression of COPD and no data exist up to now in ex-smokers with mild-moderate COPD, this study was first aimed to evaluate Nrf2 and unfolded protein response expression in peripheral blood mononuclear cells (PBMC) of mild-moderate ex-smokers with COPD compared to smoking habit-matched non-COPD subjects. Then, we tested whether oxidative stress persists after cigarette smoking cessation and whether the concentrations of oxidized phospholipids (oxidation products of the phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine [oxPAPC]) in the PBMC of the same subjects may have a causative role in determining the upregulation of Nrf2. The expression (mRNA and protein) of Nrf2 and of its related gene heme oxygenase-1 was significantly increased in COPD group without differences in the unfolded protein response. Plasma malondialdehyde, the circulating marker of oxidative stress, and oxPAPC in PBMC were significantly higher in COPD than in non-COPD subjects. The fact that the expression of p47phox, a subunit of NADPH oxidase, was increased in PBMC of COPD patients and that it was directly correlated with oxPAPC may indicate that oxPAPC may be one of the determinants of oxidative stress-induced Nrf2 upregulation. Finally, we also demonstrated that lung function inversely correlated with plasma malondialdehyde and with Nrf2 and heme oxygenase-1 mRNA expression in all subjects. Our results indicate that mild-moderate ex-smokers with COPD may be able to counteract oxidative stress by increasing the expression of Nrf2/antioxidant-response elements. Because Nrf2 failure significantly contributes to the development of COPD, our findings suggest that the possibility to prevent Nrf2 reduction may open a new scenario in helping to prevent the oxidative stress-associated lung function decline. Keywords: mild-moderate COPD, Nrf2/ARE, UPR, oxidative stress, cigarette smoking, peripheral blood mononuclear cells

Background The effectiveness of clinic-based pulmonary rehabilitation in advanced COPD is well established, but few data exist for less severe patients treated in alternative settings. The purpose of this study was to investigate whether a novel, community-based exercise program (CBE) was feasible and effective for patients with moderate COPD. Methods Nineteen patients with moderate COPD (mean FEV 1 62%) and self-reported exercise impairment were randomized to 12-weeks of progressive endurance and strength training at a local health club under the guidance of a certified personal trainer, or to continuation of unsupervised habitual physical activity. Outcomes assessed at baseline and 12 weeks included session compliance, intensity adherence, treadmill endurance time, muscle strength, dyspnea, and health status. Results Compliance was 94% and adherence was 83%. Comparisons between CBE and control groups yielded the following mean (SEM) differences in favor of CBE: endurance time 134 (74) seconds versus -59 (49) seconds (P = 0.041) and TDI 5.1 (0.8) versus -0.2 (0.5) (P < 0.001). The CBE group increased muscle strength (weight lifted) by 11.8 kilograms per subject per week of training (P < 0.001). SGRQ was not significantly changed. Conclusions We demonstrated the feasibility and effectiveness of a novel community-based exercise program involving health clubs and personal trainers for patients with moderate COPD. Trial registration ClinicalTrials.gov Identifier NCT01985529 .

Objective the study aimed to analyze the therapeutic effects of neuromuscular electrical stimulation (NMES) combined with respiratory muscle training (RMT) on patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods 135 patients with moderate/severe chronic obstructive pulmonary disease were selected as the research object and randomly selected. 72 cases were divided into rehabilitation group and 63 cases in control group. 63 healthy individuals who underwent physical examination in the same period were also included in the internal control group (blank group). Data on pulmonary function parameters (FEV 1 , FEV 1 %pred, FEV 1 /FVC ratio), blood gas analysis parameters (arterial oxygen partial pressure (PaO 2 ), carbon dioxide partial pressure (PaCO 2 ), and arterial oxygen saturation (SaO 2 )), and anxiety and depression scores were collected before and after the intervention for the RG, CG, and BG. Additionally, the COPD assessment test (CAT) scores were recorded for both the RG and CG. Results: following intervention, PaO 2 was clearly reduced, and PaCO 2 and SaO 2 were visibly higher in subjects; PaO 2 was clearly reduced, and PaCO 2 and SaO 2 were visibly higher in the RG as against the CG; Forced expiratory volume in one second (FEV 1 ), percentage of predicted FEV 1 (FEV 1 %pred), and FEV 1 /forced vital capacity (FVC) in subjects were visibly higher, and FEV 1 %pred and FEV 1 /FVC were visibly higher in the RG as against the CG; The CAT scores and anxiety and depression scores in subjects were clearly reduced, and those were clearly reduced in the RG as against the CG ( P  < 0.05). Conclusion NMES and pulmonary rehabilitation (PR) exercise training can visibly improve the lung function, oxygenation capacity, carbon dioxide exhalation, and quality of life (QoL) in COPD patients, effectively alleviating anxiety and depression.

Background There are limited data describing patients with moderate COPD exacerbations and evaluating comparative effectiveness of maintenance treatments in this patient population. The study examined COPD patients with moderate COPD exacerbations. COPD-related outcomes were compared between patients initiating fluticasone propionate-salmeterol 250/50 mcg (FSC) vs anticholinergics (ACs) following a moderate COPD exacerbation. Methods This retrospective observational study used a large administrative claims database (study period: 2003–2009) to identify and describe patients with an initial, moderate COPD exacerbation. A descriptive analysis of patients with moderate COPD exacerbations was done evaluating maintenance treatment rates, subsequent COPD exacerbation rates, and COPD-related costs during a 1-year period. A cohort analysis compared COPD exacerbation rates and associated costs during a variable-length follow-up period between patients initiating maintenance therapy with FSC or ACs. COPD exacerbations were reported as rate per 100 patient-years, and monthly costs were reported (standardized to USD 2009). COPD exacerbation rates between cohorts were evaluated using Cox proportional hazards models, and costs were analyzed using generalized linear models with log-link and gamma distribution. Results 21,524 patients with a moderate COPD exacerbation were identified. Only 25% initiated maintenance therapy, and 13% had a subsequent exacerbation. Annual costs averaged $594 per patient. A total of 2,849 treated patients (FSC = 925; AC = 1,924) were eligible for the cohort analysis. The FSC cohort had a significantly lower rate of COPD exacerbations compared to the AC cohort (20.8 vs 32.8; P  = 0.04). After adjusting for differences in baseline covariates, the FSC cohort had a 42% significantly lower risk of a COPD exacerbation (HR = 0.58; 95% CI: 0.38, 0.91). The FSC cohort incurred significantly higher adjusted pharmacy costs per patient per month by $37 (95% CI: $19, $72) for COPD-related medications vs the AC cohort. However, this increase was offset by a significant reduction in adjusted monthly medical costs per patient for the FSC vs the AC cohort ($82 vs $112; P  < 0.05). Total monthly COPD-related costs, as a result, did not differ between cohorts. Conclusions Only a quarter of patients with a moderate COPD exacerbation were subsequently treated with maintenance therapy. Initiation of FSC among those treated was associated with better clinical and economic outcomes compared to AC.

COPD is projected to be the third-leading cause of death by the year 2020. Pharmacotherapy for COPD is palliative at best, having no impact on slowing the progression of the disease. The introduction of newer therapies such as long-acting forms of bronchodilator and anticholinergic agents, together with the inclusion of inhaled corticosteroids (ICSs) in the recent Global Initiative for COPD therapeutic algorithm, have expanded the pharmacotherapy options for the treatment of COPD. This article provides a methodologic critique of the available pharmacoeconomic evidence on drug therapy for stable COPD in an effort to complement treatment guidelines and to identify any need for future pharmacoeconomic research. Relevant search strategies revealed a total of 28 economic evaluations of which 7 satisfied the study inclusion criteria. The Drummond 10-point checklist was used for the methodological critique of the economic evaluations. Five of seven pharmacoeconomic studies were conducted alongside a randomized controlled trial, and six of seven were cost-effectiveness analyses. Of the bronchodilators, the long-acting anticholinergic agent tiotropium is considered to be cost-effective relative to ipratropium. No conclusive information could be reached for the cost-effectiveness of long-acting β-agonists. A Markov analysis showed ICSs to be cost-effective for patients with moderate-to-severe COPD relative to standard care. However, assumptions of the model may bias this conclusion, and additional studies are warranted, especially compared to other treatments. The authors suggest that additional pharmacoeconomic studies be conducted to assess the cost-effectiveness of long-acting β-agonists and ICSs, between classes of bronchodilators, and between various combination therapies.

Background Debate exists regarding which endpoints most sensitively reflect day-to-day variation in chronic obstructive pulmonary disease (COPD) symptoms and are most useful in clinical practice to predict COPD exacerbations. We hypothesized that short-acting β 2 -agonist (SABA) reliever use would predict short- and long-term exacerbation risk in COPD patients. Methods We performed a retrospective analysis of data from a study (ClinicalTrials.gov registration: NCT00419744) comparing budesonide/formoterol 320/9 μg with formoterol 9 μg (both twice daily) in patients with moderate-to-very-severe COPD; reliever salbutamol 90 μg was provided. First occurrence of reliever use >4 (low), >10 (medium), and >20 (high) inhalations/day was assessed as a predictor of short-term (3-week) exacerbation risk. Mean daily reliever use in the week preceding the 2-month visit was investigated as a predictor of the long-term (10-month) exacerbation risk, using intervals of 2–5, 6–9, and ≥10 inhalations/day. Results Overall, 810 patients were included (61 % male; mean age 63.2 years; post-bronchodilator forced expiratory volume in 1 s 37.7 % of predicted). First occurrence of low, medium, or high reliever use was predictive of an exacerbation within the following 3 weeks; exacerbation risk increased significantly with increasing reliever use. Mean reliever use over 1 week was predictive of long-term exacerbation risk. Patients with mean use of 2–5, 6–9, and ≥10 inhalations/day exhibited 21 %, 67 %, and 135 % higher exacerbation rates, respectively, in the following 10 months, compared with <2 inhalations/day. Budesonide/formoterol was associated with lower short- and long-term exacerbation risk than formoterol in all reliever-use groups. Conclusions SABA reliever use is a predictor of short- and long-term exacerbation risk in moderate-to-very-severe COPD patients with a history of exacerbations receiving budesonide/formoterol or formoterol.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. It is well established that patients with mild to moderate disease represent the majority of patients with COPD, and patients with mild COPD already have measurable physiological impairment with increased morbidity and a higher risk of mortality compared with healthy non-smoking individuals. However, this subpopulation is both underdiagnosed and undertreated. In addition, most clinical trials include cohorts of patients with worse lung function and quality of life, which are very different from the milder patients usually seen in primary care. Clinical trials have shown that mild-moderate COPD patients present an improvement in lung function after treatment with long-acting bronchodilators (LABD). Inhaled therapy has also shown benefits in terms of symptoms, health-related quality of life (HRQL) and exacerbation prevention in this population. Early intervention might have also a positive effect to prevent functional impairment. Nevertheless, there is scarce evidence from randomised clinical trials and real-life studies about the importance of pharmacological treatment in early stages of COPD to improve long-term outcomes. New concepts such as clinically important deterioration may help to investigate the impact of interventions on the natural history of the disease.