Research priorities to address the global burden of chronic obstructive pulmonary disease (COPD) in the next decade.

BACKGROUND: The global prevalence of chronic obstructive pulmonary disease (COPD) has increased markedly in recent decades. Given the scarcity of resources available to address global health challenges and respiratory medicine being relatively under-invested in, it is important to define research priorities for COPD globally. In this paper, we aim to identify a ranked set of COPD research priorities that need to be addressed in the next 10 years to substantially reduce the global impact of COPD. METHODS: We adapted the Child Health and Nutrition Research Initiative (CHNRI) methodology to identify global COPD research priorities. RESULTS: 62 experts contributed 230 research ideas, which were scored by 34 researchers according to six pre-defined criteria: answerability, effectiveness, feasibility, deliverability, burden reduction, and equity. The top-ranked research priority was the need for new effective strategies to support smoking cessation. Of the top 20 overall research priorities, six were focused on feasible and cost-effective pulmonary rehabilitation delivery and access, particularly in primary/community care and low-resource settings. Three of the top 10 overall priorities called for research on improved screening and accurate diagnostic methods for COPD in low-resource primary care settings. Further ideas that drew support involved a better understanding of risk factors for COPD, development of effective training programmes for health workers and physicians in low resource settings, and evaluation of novel interventions to encourage physical activity. CONCLUSIONS: The experts agreed that the most pressing feasible research questions to address in the next decade for COPD reduction were on prevention, diagnosis and rehabilitation of COPD, especially in low resource settings. The largest gains should be expected in low- and middle-income countries (LMIC) settings, as the large majority of COPD deaths occur in those settings. Research priorities identified by this systematic international process should inform and motivate policymakers, funders, and researchers to support and conduct research to reduce the global burden of COPD.

Sex differences between women and men with COPD: A new analysis of the 3CIA study.

BACKGROUND: There is partial evidence that COPD is expressed differently in women than in men, namely on symptoms, pulmonary function, exacerbations, comorbidities or prognosis. There is a need to improve the characterization of COPD in females. METHODS: We obtained and pooled data of 17 139 patients from 22 COPD cohorts and analysed the clinical differences by sex, establishing the relationship between these characteristics in women and the prognosis and severity of the disease. Comparisons were established with standard statistics and survival analysis, including crude and multivariate Cox-regression analysis. RESULTS: Overall, 5355 (31.2%) women were compared with men with COPD. Women were younger, had lower pack-years, greater FEV1%, lower BMI and a greater number of exacerbations (all p < 0.05). On symptoms, women reported more dyspnea, equal cough but less expectoration (p < 0.001). There were no differences in the BODE index score in women (2.4) versus men (2.4) (p = 0.5), but the distribution of all BODE components was highly variable by sex within different thresholds of BODE. On prognosis, 5-year survival was higher in COPD females (86.9%) than in males (76.3%), p < 0.001, in all patients and within each of the specific comorbidities that we assessed. The crude and adjusted RR and 95% C.I. for death in males was 1.82 (1.69-1.96) and 1.73 (1.50-2.00), respectively. CONCLUSIONS: COPD in women has some characteristic traits expressed differently than compared to men, mainly with more dyspnea and COPD exacerbations and less phlegm, among others, although long-term survival appears better in female COPD patients.

Cardiovascular Studies in Patients with Chronic Obstructive Pulmonary Disease Due to Biomass Smoke or Tobacco.

BACKGROUND AND OBJECTIVE: The cardiovascular effects of biomass smoke exposure in patients with chronic obstructive pulmonary disease are not well characterized, and few studies have assessed the possible differences between patients with disease caused by biomass smoke and tobacco. The aim of this study was to search for differences in cardiovascular variables between both types of the disease. METHODS: Twenty subjects (15 men, 5 women) with chronic obstructive pulmonary disease caused by tobacco were matched one to one for sex, age, and forced expiratory volume in 1 s to 20 patients with biomass-related disease. Echocardiography and carotid ultrasound studies were performed. Flow-mediated endothelium-dependent vasodilatation and endothelium-independent vasodilatation were also measured. RESULTS: There were no significant differences between groups in any of the echocardiographic variables, nor in the intima-media carotid thickness, the number of carotid plaques, or the percentage of endothelium-dependent or endothelium-independent vasodilation. A high percentage of patients in both groups showed an abnormal flow-mediated endothelium-dependent vasodilatation pattern. CONCLUSION: The study does not support the hypothesis of a different cardiovascular effect of biomass or tobacco smoke exposure in patients with chronic obstructive pulmonary disease. Cardiovascular comorbidity should be assessed in patients with biomass-associated disease, similarly to subjects with tobacco-related disease.

Recent lung cancer mortality trends in Europe: effect of national smoke-free legislation strengthening.

The impact of smoke-free legislation within European Union (EU) countries on lung cancer mortality has not been evaluated to date. We aimed to determine lung cancer mortality trends in the EU-27 by sex, age, and calendar year for the period of 1994 and 2012, and relate them with changes in tobacco legislation at the national level. Deaths by Eurostat in each European country were analyzed, focusing on ICD-10 codes C33 and C34 from the years 1994 to 2012. Age-standardized mortality rates (ASR) were estimated separately for women and men in the EU-27 total and within country for each one of the years studied, and the significance of changing trends was estimated by joinpoint regression analysis, exploring lag times after initiation of smoke-free legislation in every country, if any. From 1994 to 2012, there were 4 681 877 deaths from lung cancer in Europe (3 491 607 in men and 1 190 180 in women) and a nearly linear decrease in mortality rates because of lung cancer in men from was observed1994 to 2012, mirrored in women by an upward trend, narrowing the sex gap during the study period from 5.1 in 1994 to 2.8 in 2012. Joinpoint regression analysis identified a number of trend changes over time, but it appears that they were unrelated to the implementation of smoke-free legislations. A few years after the introduction of smoke-free legislations across Europe, trends of lung cancer mortality trends have not changed.

Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. METHODS: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, postbronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. MAIN OUTCOMES: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. FINDINGS: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. CONCLUSIONS: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed.

Differences in systemic inflammation between cigarette and biomass smoke-induced COPD.

BACKGROUND AND OBJECTIVE: It is known that biomarkers of systemic inflammation are raised in COPD caused by tobacco (T-COPD) compared with healthy controls, but there is less information on the inflammatory status of subjects with COPD caused by biomass smoke (B-COPD). In addition, the possible (if any) differences in inflammation between both types of the disease are still not well known. The aim of this study was to assess the inflammatory profile in B-COPD and T-COPD. METHODS: A total of 20 subjects (15 men and five women) with T-COPD were matched one to one for sex, age and forced expiratory volume in 1 s (FEV1) to 20 B-COPD patients. In all, 20 sex-matched healthy subjects with normal lung function without smoking history or biomass exposure were included as controls. The following biomarkers were measured: exhaled nitric oxide, serum IL-6, IL-8, IL-5, IL-13, periostin, surfactant protein-P, TNF-α, IgE, erythrocyte sedimentation rate, C-reactive protein and fibrinogen. Complete blood count was also obtained. RESULTS: The age of the subjects was 70.2±7.9 years and FEV1% was 56.2%±14.6%. Most inflammatory biomarkers were higher in both types of COPD than in healthy controls. IL-6, IL-8 and IL-5 were significantly higher in T-COPD than in B-COPD, without other significant differences. CONCLUSION: Both types of COPD are associated with high levels of systemic inflammation biomarkers. T-COPD patients have a higher systemic inflammatory status than the patients with B-COPD.

Guideline Adherence in Outpatient Clinics for Chronic Obstructive Pulmonary Disease: Results from a Clinical Audit.

OBJECTIVES: Previous clinical audits of COPD have provided relevant information about medical intervention in exacerbation admissions. The present study aims to evaluate adherence to current guidelines in COPD through a clinical audit. METHODS: This is a pilot clinical audit performed in hospital outpatient respiratory clinics in Andalusia, Spain (eight provinces with more than 8 million inhabitants), including 9 centers (20% of the public centers in the area) between 2013 and 2014. Cases with an established diagnosis of COPD based on risk factors, clinical symptoms, and a post-bronchodilator FEV1/FVC ratio of less than 0.70 were deemed eligible. The performance of the outpatient clinics was benchmarked against three guidance documents available at the time of the audit. The appropriateness of the performance was categorized as excellent (>80%), good (60-80%), adequate (40-59%), inadequate (20-39%), and highly inadequate (<20%). RESULTS: During the audit, 621 clinical records were audited. Adherence to the different guidelines presented a considerable variability among the different participating hospitals, with an excellent or good adherence for symptom recording, MRC or CAT use, smoking status evaluation, spirometry, or bronchodilation therapy. The most outstanding areas for improvement were the use of the BODE index, the monitoring of treatments, the determination of alpha1-antitrypsin, the performance of exercise testing, and vaccination recommendations. CONCLUSIONS: The present study reflects the situation of clinical care for COPD patients in specialized secondary care outpatient clinics. Adherence to clinical guidelines shows considerable variability in outpatient clinics managing COPD patients, and some aspects of the clinical care can clearly be improved.

Identification of oxidative stress related proteins as biomarkers for lung cancer and chronic obstructive pulmonary disease in bronchoalveolar lavage.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Determination of inflammatory biomarkers in patients with COPD: a comparison of different assays.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory pulmonary disorder with systemic inflammatory manifestations that are mediated by circulating acute-phase reactants. This study compared an enzyme-linked immunosorbent assay (ELISA) to a nephelometric technique for the measurement of serum C-reactive protein (CRP) and serum amyloid A (SAA) and investigated how the choice of assay influenced the estimation of inflammation in patients with stable COPD. METHODS: CRP and SAA concentrations measured by ELISA and nephelometry in 88 patients with COPD and 45 control subjects were used to evaluate the performance of these methods in a clinical setting. RESULTS: With both assays, the concentrations of CRP and SAA were higher in COPD patients than in controls after adjustment for age and sex. There was a moderate correlation between the values measured by ELISA and those measured by nephelometry (logCRP: r = 0.55, p < 0.001; logSAA: r = 0.40, p < 0.001). However, the concentrations of biomarkers determined by nephelometry were significantly higher than those obtained with ELISA for CRP (mean difference = 2.7 (9.4) mg/L) and SAA (mean difference = 0.31 (14.3) mg/L). CONCLUSION: Although the serum CRP and SAA concentrations measured by ELISA and nephelometry correlated well in COPD patients, the ELISA values tended to be lower for CRP and SAA when compared with nephelometric measurements. International standardization of commercial kits is required before the predictive validity of inflammatory markers for patients with COPD can be effectively assessed in clinical practice.