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BackgroundRisk factors for COPD in high-income settings are well understood; however, less attention has been paid to contributors of COPD in low-income and middle-income countries (LMICs) such as pulmonary tuberculosis. We sought to study the association between previous tuberculosis disease and COPD by using pooled population-based cross-sectional data in 13 geographically diverse, low-resource settings.MethodsWe pooled six cohorts in 13 different LMIC settings, 6 countries and 3 continents to study the relationship between self-reported previous tuberculosis disease and lung function outcomes including COPD (defined as a postbronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) below the lower limit of normal). Multivariable regressions with random effects were used to examine the association between previous tuberculosis disease and lung function outcomes.ResultsWe analysed data for 12 396 participants (median age 54.0 years, 51.5% male); 332 (2.7%) of the participants had previous tuberculosis disease. Overall prevalence of COPD was 8.8% (range 1.7%–15.5% across sites). COPD was four times more common among those with previous tuberculosis disease (25.7% vs 8.3% without previous tuberculosis disease, p1(−0.70, 95% CI −0.84 to −0.55), FVC (−0.44, 95% CI −0.59 to −0.29) and the FEV1:FVC ratio (−0.63, 95% CI −0.76 to −0.51) when compared with those without previous tuberculosis disease.ConclusionsPrevious tuberculosis disease is a significant and under-recognised risk factor for COPD and poor lung function in LMICs. Better tuberculosis control will also likely reduce the global burden of COPD.

Background/Objectives Abnormal body composition is an independent determinant of COPD outcomes. To date, it is already known that patient stratification into body composition phenotypes are associated with important outcomes, such as exercise capacity and inflammation, but there are no data comparing physical activity and muscle strength among these phenotypes. Thus, the aim of this study was to compare clinical characteristics and physical function in patients with COPD stratified into body composition phenotypes.Subjects/Methods Two-hundred and seventy stable COPD patients were classified according to the 10th and 90th percentiles of sex-age-BMI-specific reference values for fat-free and fat mass indexes into four groups: Normal body composition (NBC), Obese, Sarcopenic, and Sarcopenic-obese (SO). Patients underwent assessment of exercise capacity, peripheral and respiratory muscle strength, physical activity, dyspnea severity, functional status, and symptoms of anxiety and depression.Results The prevalence of patients classified as NBC, Obese, Sarcopenic, and SO was 39%, 13%, 21%, or 27%, respectively. SO presented lower 6MWT compared with NBC (P 0.16). Sarcopenic and SO groups had, respectively, 7.8 [95% CI: 1.6-37.7] and 9.5 [2.2-41.7] times higher odds to have a 6MWT equal or lower to 350 meters.Conclusions Body composition phenotypes are associated with physical function in patients with COPD. Sarcopenic-obese patients were the most impaired.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; COPD led to 3.2 million deaths in 2017, a toll expected to reach 4.4 million yearly by 2040.1,2 With a worldwide prevalence of 10.1%, COPD afflicts many people in low-income, middle-income, and wealthy countries (Figure 1), and years of life lost prematurely increased 13.2% between 2007 and 2017.1 Although COPD has traditionally been considered a disease that affects men, in some countries, the prevalence and associated mortality are higher among women than among men. In this review, we update the clinical face of COPD, concentrating on the pulmonary aspects of the disease, which also affects many other organ systems. The pathogenesis of COPD is discussed in a companion article by Agustí and Hogg in this issue of the Journal,3 and the review of muco-obstructive lung diseases in a recent issue of the Journal4 complements this article.

Introduction: Distinct pathologies can cause chronic obstructive pulmonary disease (COPD). Emphysema is a COPD-phenotype characterized by destruction of lung parenchyma. Alpha-1 antitrypsin deficiency (AATD) is a genetic cause of emphysema, whereas smoking is the most important risk factor of non-AATD emphysema. A general underappreciation of non-AATD emphysema has hampered progress in the field, and clinical guidelines have prohibited the use of emphysema as a diagnosis. Non-AATD emphysema, however, is far from irrelevant as it associates with dyspnea, reduced exercise capacity and relevant outcome measures. Areas covered: Mechanisms underlying enhanced tissue loss in emphysema are protease/antiprotease imbalance, increased oxidative stress, several fundamental cell biological processes such as programmed cell death and autophagy, and impaired repair mechanisms. Therapeutic options for emphysema vary from smoking cessation to lung volume reduction. Current pharmacological treatments have less favorable effects in emphysematous than in non-emphysematous COPD patients. Expert opinion: We advocate the acknowledgment of non-AATD emphysema as a clinical diagnosis and propose to end the era of bringing all pathologies that may lead to chronic airflow limitation together under the umbrella-term of COPD. Decelerating proteolysis and restoring damage should be main targets in emphysema. Vitamin A/K, hyaluronan, copper and roflumilast are promising candidates.

Introduction: Distinct pathologies can cause chronic obstructive pulmonary disease (COPD). Emphysema is a COPD-phenotype characterized by destruction of lung parenchyma. Alpha-1 antitrypsin deficiency (AATD) is a genetic cause of emphysema, whereas smoking is the most important risk factor of non-AATD emphysema. A general underappreciation of non-AATD emphysema has hampered progress in the field, and clinical guidelines have prohibited the use of emphysema as a diagnosis. Non-AATD emphysema, however, is far from irrelevant as it associates with dyspnea, reduced exercise capacity and relevant outcome measures. Areas covered: Mechanisms underlying enhanced tissue loss in emphysema are protease/antiprotease imbalance, increased oxidative stress, several fundamental cell biological processes such as programmed cell death and autophagy, and impaired repair mechanisms. Therapeutic options for emphysema vary from smoking cessation to lung volume reduction. Current pharmacological treatments have less favorable effects in emphysematous than in non-emphysematous COPD patients. Expert opinion: We advocate the acknowledgment of non-AATD emphysema as a clinical diagnosis and propose to end the era of bringing all pathologies that may lead to chronic airflow limitation together under the umbrella-term of COPD. Decelerating proteolysis and restoring damage should be main targets in emphysema. Vitamin A/K, hyaluronan, copper and roflumilast are promising candidates.

Lung cancer, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD) are expected to cause most deaths by 2050. State-of-the-art computed tomography (CT) allows early detection of lung cancer and simultaneous evaluation of imaging biomarkers for the early stages of COPD, based on pulmonary density and bronchial wall thickness, and of CAD, based on the coronary artery calcium score (CACS), at low radiation dose. To determine cut-off values for positive tests for elevated risk and presence of disease is one of the major tasks before considering implementation of CT screening in a general population. The ImaLife (Imaging in Lifelines) study, embedded in the Lifelines study, is designed to establish the reference values of the imaging biomarkers for the big three diseases in a well-defined general population aged 45 years and older. In total, 12,000 participants will undergo CACS and chest acquisitions with latest CT technology. The estimated percentage of individuals with lung nodules needing further workup is around 1–2%. Given the around 10% prevalence of COPD and CAD in the general population, the expected number of COPD and CAD is around 1000 each. So far, nearly 4000 participants have been included. The ImaLife study will allow differentiation between normal aging of the pulmonary and cardiovascular system and early stages of the big three diseases based on low-dose CT imaging. This information can be finally integrated into personalized precision health strategies in the general population.

Ahmed S Sadaka,1,3 Andrew J Montgomery,2 Sahar M Mourad,3 Michael I Polkey,1 Nicholas S Hopkinson1 1NIHR Respiratory Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, Respiratory Medicine, London, UK; 2Royal Brompton and Harefield NHS Foundation Trust, London, UK; 3Alexandria University Faculty of Medicine, Chest Department, Alexandria, Egypt Purpose: Hypoxemia is associated with more severe lung disease and worse outcomes. In some patients with chronic obstructive lung diseases who desaturate on exertion, supplemental oxygen improves exercise capacity. The clinical significance of this exercise response to oxygen supplementation is not known.Patients and methods: We identified chronic obstructive lung disease patients at our center who underwent a 6-minute walking test (6MWT) for ambulatory oxygen assessment and who desaturated breathing air and therefore had an additional walk test on supplemental oxygen, between August 2006 and June 2016. Responders were defined as walking ≥26 m further with oxygen. Survival was determined up to February 1, 2017. We compared survival in oxygen responders and nonresponders in patients with obstructive lung diseases.Results: One hundred and seventy-four patients were included in the study, median age 70 years. Seventy-seven (44.3%) of the patients were oxygen responders. Borg dyspnea score improved by 1.4 (±1.4) units (P

The clinical manifestations of chronic obstructive pulmonary disease (COPD) reflect an aggregate of multiple pulmonary and extrapulmonary processes. It is increasingly clear that full assessment of these processes is essential to characterize disease burden and to tailor therapy. Medical imaging has advanced such that it is now possible to obtain in vivo insight in the presence and severity of lung disease-associated features. In this review, we have assembled data from multiple disciplines of medical imaging research to review the role of imaging in characterization of COPD. Topics include imaging of the lungs, body composition, and extrapulmonary tissue metabolism. The primary focus is on imaging modalities that are widely available in clinical care settings and that potentially contribute to describing COPD heterogeneity and enhance our insight in underlying pathophysiological processes and their structural and functional effects.

The clinical manifestations of chronic obstructive pulmonary disease (COPD) reflect an aggregate of multiple pulmonary and extrapulmonary processes. It is increasingly clear that full assessment of these processes is essential to characterize disease burden and to tailor therapy. Medical imaging has advanced such that it is now possible to obtain in vivo insight in the presence and severity of lung disease-associated features. In this review, we have assembled data from multiple disciplines of medical imaging research to review the role of imaging in characterization of COPD. Topics include imaging of the lungs, body composition, and extrapulmonary tissue metabolism. The primary focus is on imaging modalities that are widely available in clinical care settings and that potentially contribute to describing COPD heterogeneity and enhance our insight in underlying pathophysiological processes and their structural and functional effects.

Purpose of reviewThe current review summarizes ongoing developments in personalized medicine and precision medicine in chronic obstructive pulmonary disease (COPD). Our current approach is far away of personalized management algorithms as current recommendations for COPD are largely based on a reductionist disease description, operationally defined by results of spirometry.Recent findingsBesides precision medicine developments, a personalized medicine approach in COPD is described based on a holistic approach of the patient and considering illness as the consequence of dynamic interactions within and between multiple interacting and self-adjusting systems. Pulmonary rehabilitation is described as a model of personalized medicine. Largely based on current understanding of inflammatory processes in COPD, targeted interventions in COPD are reviewed. Augmentation therapy for alpha-1-antitrypsine deficiency is described as model of precision medicine in COPD based in profound understanding of the related genetic endotype.SummaryFuture developments of precision medicine in COPD require identification of relevant endotypes combined with proper identification of phenotypes involved in the complex and heterogeneous manifestations of COPD.

Purpose of review The current review summarizes ongoing developments in personalized medicine and precision medicine in chronic obstructive pulmonary disease (COPD). Our current approach is far away of personalized management algorithms as current recommendations for COPD are largely based on a reductionist disease description, operationally defined by results of spirometry. Recent findings Besides precision medicine developments, a personalized medicine approach in COPD is described based on a holistic approach of the patient and considering illness as the consequence of dynamic interactions within and between multiple interacting and self-adjusting systems. Pulmonary rehabilitation is described as a model of personalized medicine. Largely based on current understanding of inflammatory processes in COPD, targeted interventions in COPD are reviewed. Augmentation therapy for alpha-1-antitrypsine deficiency is described as model of precision medicine in COPD based in profound understanding of the related genetic endotype. Summary Future developments of precision medicine in COPD require identification of relevant endotypes combined with proper identification of phenotypes involved in the complex and heterogeneous manifestations of COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (similar to 6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 x 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Background: The rate of lung-function decline in chronic obstructive pulmonary disease (COPD) varies substantially among individuals. We sought to develop and validate an individualized prediction model for forced expiratory volume at 1 second (FEV1) in current smokers with mild-to-moderate COPD.Methods: Using data from a large long-term clinical trial (the Lung Health Study), we derived mixed-effects regression models to predict future FEV1 values over 11 years according to clinical traits. We modelled heterogeneity by allowing regression coefficients to vary across individuals. Two independent cohorts with COPD were used for validating the equations.Results: We used data from 5594 patients (mean age 48.4 yr, 63% men, mean baseline FEV1 2.75 L) to create the individualized prediction equations. There was significant between-individual variability in the rate of FEV1 decline, with the interval for the annual rate of decline that contained 95% of individuals being -124 to -15 mL/yr for smokers and -83 to 15 mL/yr for sustained quitters. Clinical variables in the final model explained 88% of variation around follow-up FEV1. The C statistic for predicting severity grades was 0.90. Prediction equations performed robustly in the 2 external data sets.Interpretation: A substantial part of individual variation in FEV1 decline can be explained by easily measured clinical variables. The model developed in this work can be used for prediction of future lung health in patients with mild-to-moderate COPD.Trial registration: Lung Health Study ClinicalTrials.gov, no. NCT00000568; Pan-Canadian Early Detection of Lung Cancer Study ClinicalTrials.gov, no. NCT00751660

Maarten van den Berge,1,2 René Aalbers,31Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, 2GRIAC Research Institute, University Medical Center Groningen, University of Groningen, 3Department of Pulmonary Diseases, Martini Hospital, Groningen, the Netherlands Abstract: It is increasingly recognized that both asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases with a large inter-individual variability with respect to their clinical expression, disease progression, and responsiveness to the available treatments. The introduction of asthma–COPD overlap syndrome (ACOS) may lead to a better clinical characterization and improved treatment of patients with obstructive airways disease. However, it is still in its early phase and several improvements will have to be made. First, a clear definition of ACOS and preferably also its sub-phenotypes, eg, asthma–ACOS and COPD–ACOS, is urgently needed. That would also allow researchers to design clinical studies in well-defined patients. The latter is important since the interpretation of clinical studies performed so far is hampered by the use of many different definitions of ACOS. Second, future studies are needed to investigate the role of state-of-the-art techniques such as computed tomography, genetics, and genomics in the phenotyping of patients with obstructive airways disease, ie, asthma, COPD, and ACOS. Third, longitudinal studies are now needed to better define the clinical implications of ACOS with respect to the long-term outcome and treatment of ACOS and its sub-phenotypes compared to only asthma or COPD. Keywords: ACOS, asthma, COPD, inflammation, remodeling, overlap phenotype

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci., Supported in part by the Intramural Research Program of the National Institutes of Health, NIEHS. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute Grant R01HL105756

Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14–15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4–11q14.1 (LOD = 3.71) and 5q14.3–5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF)

The Dutch hypothesis was first articulated in 1961, when many novel and advanced scientific techniques were not available, such as genomics techniques for pinpointing genes, gene expression, lipid and protein profiles, and the microbiome. In addition, computed tomographic scans and advanced analysis techniques to dissect (small) airways disease and emphysema were not available. At that time, the group of researchers under the visionary guidance of Professor N. G. M. Orie put forward that both genetic and environmental factors can determine whether one would have airway obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Moreover, they stipulated that the phenotype of obstructive airway disease could be affected by sex and changes with aging. Orie and colleagues' call to carefully phenotype patients with obstructive airways diseases has been adopted by many current researchers in an attempt to determine the heterogeneity of both asthma andCOPD to better define these diseases and optimize their treatment. The founders of the Dutch hypothesis were far ahead of their time, and we can learn from their insights. We should fully characterize all patients in our clinical practice and not just state that they have asthma, COPD, or asthma and COPD overlap syndrome. This detailed phenotyping can help in understanding these obstructive airway diseases and provide guidance for disease management.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Age and smoking are common risk factors for COPD and other illnesses, often leading COPD patients to demonstrate multiple coexisting comorbidities. COPD exacerbations and comorbidities contribute to the overall severity in individual patients. Clinical trials investigating the treatment of COPD routinely exclude patients with multiple comorbidities or advanced age. Clinical practice guidelines for a specific disease do not usually address comorbidities in their recommendations. However, the management and the medical intervention in COPD patients with comorbidities need a holistic approach that is not clearly established worldwide. This holistic approach should include the specific burden of each comorbidity in the COPD severity classification scale. Further, the pharmacological and nonpharmacological management should also include optimal interventions and risk factor modifications simultaneously for all diseases. All health care specialists in COPD management need to work together with professionals specialized in the management of the other major chronic diseases in order to provide a multidisciplinary approach to COPD patients with multiple diseases. In this review, we focus on the major comorbidities that affect COPD patients. We present an overview of the problems faced, the reasons and risk factors for the most commonly encountered comorbidities, and the burden on health care costs. We also provide a rationale for approaching the therapeutic options of the COPD patient afflicted by comorbidity.

Background: Dynamic hyperinflation due to increased respiratory frequency during exercise is associated with limitations in exercise capacity in patients with moderately severe chronic obstructive pulmonary disease (COPD). Objectives: The present study assessed whether the manually paced tachypnea (MPT) test, sitting at rest, induces dynamic hyperinflation correlating with exercise capacity in patients with very severe COPD. Methods: Dynamic hyperinflation was induced by the MPT test, using a breathing frequency of 40/min for 1 min. Dynamic hyperinflation was defined as a ‘change' in inspiratory capacity (IC) before and directly after the MPT test. At baseline, static hyperinflation by body plethysmography was measured, as well as the 6-min walking test and spirometry. Results: We studied 74 patients with severe COPD (age 59 ± 9 years, FEV1 28 ± 10% predicted). All patients tolerated the MPT test well. It induced a significant decrease in IC: -0.65 ± 0.33 liters, p < 0.001, correlating with the 6-min walking distance (rho = -0.246, p = 0.034). Static hyperinflation [IC/total lung capacity (TLC)] at baseline correlated stronger with the 6-min walking distance (r = 0.582, p < 0.001). Multiple regression analysis showed that IC/TLC, but not dynamic hyperinflation, was the only independent predictor of walking distance. Conclusions: In patients with very severe COPD, dynamic hyperinflation measurement by the MPT test is feasible and contributes less importantly to exercise performance than static hyperinflation.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Age and smoking are common risk factors for COPD and other illnesses, often leading COPD patients to demonstrate multiple coexisting comorbidities. COPD exacerbations and comorbidities contribute to the overall severity in individual patients. Clinical trials investigating the treatment of COPD routinely exclude patients with multiple comorbidities or advanced age. Clinical practice guidelines for a specific disease do not usually address comorbidities in their recommendations. However, the management and the medical intervention in COPD patients with comorbidities need a holistic approach that is not clearly established worldwide. This holistic approach should include the specific burden of each comorbidity in the COPD severity classification scale. Further, the pharmacological and nonpharmacological management should also include optimal interventions and risk factor modifications simultaneously for all diseases. All health care specialists in COPD management need to work together with professionals specialized in the management of the other major chronic diseases in order to provide a multidisciplinary approach to COPD patients with multiple diseases. In this review, we focus on the major comorbidities that affect COPD patients. We present an overview of the problems faced, the reasons and risk factors for the most commonly encountered comorbidities, and the burden on health care costs. We also provide a rationale for approaching the therapeutic options of the COPD patient afflicted by comorbidity.

Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough. On the basis of age and smoking history, it is often easy to distinguish between asthma and COPD. However, some patients have features compatible with both diseases. Because clinical studies typically exclude these patients, their underlying disease mechanisms and appropriate treatment remain largely uncertain. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the American Thoracic Society, convened a workshop of investigators in San Francisco, California on May 14, 2016. At the workshop, current understanding of asthma-COPD overlap was discussed among clinicians, pathologists, radiologists, epidemiologists, and investigators with expertise in asthma and COPD. They considered knowledge gaps in our understanding of asthma-COPD overlap and identified strategies and research priorities that will advance its understanding. This report summarizes those discussions.

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10(-8)) and PPP4R4/SERPINA1 (P = 1.01 X 10(-8)) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, similar to 0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

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Background Epigenetic variations in peripheral blood have potential as biomarkers for disease. This systematic review assesses the association of lung function and chronic obstructive pulmonary disease (COPD) with DNA methylation profiles in peripheral blood from population-based studies. Methods Online databases Medline, Embase, and Web of Science were searched. Google Scholar was searched to identify grey literature. After removing duplicate articles, 1155 articles were independently screened by two investigators. Peer reviewed reports on population-based studies that examined peripheral blood DNA methylation in participants with measured lung function (FEV1, FEV1/FVC ratio) or known COPD status were selected for full-text review. Six articles were suitable for inclusion. Information regarding study characteristics, designs, methodologies and conclusions was extracted. A narrative synthesis was performed based on published results. Results Three of the six articles assessed the association of COPD with DNA methylation, and two of these also included associations with lung function. Overall, five reports examined the association of lung function with DNA methylation profiles. Five of the six articles reported ‘significant’ results. However, no consistent CpG sites were identified across studies for COPD status or lung function values. Conclusions DNA methylation patterns in peripheral blood from individuals with reduced lung function or COPD may be different to those in people with normal lung function. However, this systematic review did not find any consistent associations of lung function or COPD with differentially methylated CpG sites. Large studies with a longitudinal design to address reverse causality may prove a more fruitful area of research. Trial registration PROSPERO 2016: CRD42016037352. Electronic supplementary material The online version of this article (doi:10.1186/s12890-017-0397-3) contains supplementary material, which is available to authorized users.

RationalePulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.ObjectivesTo complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.MethodsWe determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.Measurements and main resultsAmong 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema.ConclusionsOur results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.

Patients with chronic obstructive pulmonary disease (COPD) present with a variety of symptoms that significantly impair health-related quality of life. Despite this, COPD treatment and its management are mainly based on lung function assessments. There is increasing evidence that conventional lung function measures alone do not correlate well with COPD symptoms and their associated impact on patients' everyday lives. Instead, symptoms should be assessed routinely, preferably by using patient-centered questionnaires that provide a more accurate guide to the actual burden of COPD. Numerous questionnaires have been developed in an attempt to find a simple and reliable tool to use in everyday clinical practice. In this paper, we review three such patient-reported questionnaires recommended by the latest Global Initiative for Chronic Obstructive Lung Disease guidelines, ie, the modified Medical Research Council questionnaire, the clinical COPD questionnaire, and the COPD Assessment Test, as well as other symptom-specific questionnaires that are currently being developed.

Chronic obstructive pulmonary disease is a public health problem that results in high morbidity, disability and mortality. Comorbidities are highly prevalent in COPD patients because of aging, common risk factors and pathways, rising mortality, and disability. In this review article we present the most prevalent co-morbidities in COPD patients, we face the issue of multimorbidity and discuss the practical management approach relevant to chest physicians and general practitioners. Issues on comorbidities management according to general guidelines as well as their implications for COPD are raised. The aim is to give clinicians an easy update with specific recommendations for each comorbidity. The implications of several medications used for comorbidities in COPD in terms of benefits, concerns, medication preference, medication avoidance and contraindications are also discussed.

The 2001 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report defined five stages of spirometric severity (post-bronchodilator FEV1/FVC≥0.7): 0, and 1 (mild) to 4 (very severe). GOLD Stage 0 was defined by chronic cough and sputum production or chronic mucus hypersecretion (CMH) alone with preserved FEV1/FVC. Subsequently, GOLD 0 was discarded as further evidence of COPD development in subjects with GOLD 0 was not more likely to develop. When expanding symptomatic burden in GOLD 0 to include other chronic respiratory symptoms, such as dyspnea, wheeze, poor quality of life, limited physical activity, and ‘COPD exacerbations-like’ events needing health resources, symptomatic smokers with normal FEV1 resulted in larger risk of death. We review the evidence supporting a relationship between an increased symptom burden, long-term FEV1 decline and development of COPD. We also address the evidence for the presence of respiratory symptoms with normal FEV1 in smokers as a potential clinical entity. This subset of symptomatic patients encompasses a compelling category of smokers with normal spirometry but increased risk for poor outcomes. What exactly these symptomatic patients with intact FEV1 represent remains unclear. Whether they exemplify smoking-induced just a broadening of respiratory abnormalities or a distinct clinical entity that precedes the development of COPD or both remains unknown. Other aims, such as providing information on pathogenesis and future areas of research, are just as vital. What ultimately prevails however is the importance of the public health message to the frightening presence of chronic respiratory symptoms in the whole population.

Background Bronchodilators are a central component for treating exacerbations of chronic obstructive pulmonary disease (COPD) all over the world. Clinicians often use nebulisers as a mode of delivery, especially in the acute setting, and many patients seem to benefit from them. However, evidence supporting this choice from systematic analysis is sparse, and available data are frequently biased by the inclusion of asthma patients. Therefore, there is little or no formal guidance regarding the mode of delivery, which has led to a wide variation in practice between and within countries and even among doctors in the same hospital. We assessed the available randomised controlled trials (RCTs) to help guide practice in a more uniform way. Objectives To compare the effects of nebulisers versus pressurised metered dose inhalers (pMDI) plus spacer or dry powder inhalers (DPI) in bronchodilator therapy for exacerbations of COPD. Search methods We searched the Cochrane Airways Group Trial Register and reference lists of articles up to 1 July 2016. Selection criteria RCTs of both parallel and cross-over designs. We included RCTs during COPD exacerbations, whether measured during hospitalisation or in an outpatient setting. We excluded RCTs involving mechanically ventilated patients due to the different condition of both patients and airways in this setting. Data collection and analysis Two review authors independently assessed studies for inclusion, extracted data and assessed the risk of bias. We report results with 95% confidence intervals (CIs). Main results This review includes eight studies with a total of 250 participants comparing nebuliser versus pMDI plus spacer treatment. We identified no studies comparing DPI with nebulisers. We found two studies assessing the primary outcome of 'change in forced expiratory volume in one second (FEV1) one hour after dosing'. We could not pool these studies, but both showed a non-significant difference in favour of the nebuliser group, with similar frequencies of serious adverse events. For the secondary outcome, 'change in FEV1 closest to one hour after dosing': we found a significant difference of 83 ml (95% CI 10 to 156, P = 0.03) in favour of nebuliser treatment. For the secondary outcome of adverse events, we found a non-significant odds ratio of 1.65 (95% CI 0.42 to 6.48) in favour of the pMDI plus spacer group. Authors' conclusions There is a lack of evidence in favour of one mode of delivery over another for bronchodilators during exacerbations of COPD. We found no difference between nebulisers versus pMDI plus spacer regarding the primary outcomes of FEV1 at one hour and safety. For the secondary outcome 'change in FEV1 closest to one hour after dosing' during an exacerbation of COPD, we found a greater improvement in FEV1 when treating with nebulisers than with pMDI plus spacers. A limited amount of data are available (eight studies involving 250 participants). These studies were difficult to pool, of low quality and did not provide enough evidence to favour one mode of delivery over another. No data of sufficient quality have been published comparing nebulisers versus DPIs in this setting. More studies are required to assess the optimal mode of delivery during exacerbations of COPD.

BackgroundBronchodilators are a central component for treating exacerbations of chronic obstructive pulmonary disease (COPD) all over the world. Clinicians often use nebulisers as a mode of delivery, especially in the acute setting, and many patients seem to benefit from them. However, evidence supporting this choice from systematic analysis is sparse, and available data are frequently biased by the inclusion of asthma patients. Therefore, there is little or no formal guidance regarding the mode of delivery, which has led to a wide variation in practice between and within countries and even among doctors in the same hospital. We assessed the available randomised controlled trials (RCTs) to help guide practice in a more uniform way.ObjectivesTo compare the effects of nebulisers versus pressurised metered dose inhalers (pMDI) plus spacer or dry powder inhalers (DPI) in bronchodilator therapy for exacerbations of COPD.Search methodsWe searched the Cochrane Airways Group Trial Register and reference lists of articles up to 1 July 2016.Selection criteriaRCTs of both parallel and cross-over designs. We included RCTs during COPD exacerbations, whether measured during hospitalisation or in an outpatient setting. We excluded RCTs involving mechanically ventilated patients due to the different condition of both patients and airways in this setting.Data collection and analysisTwo review authors independently assessed studies for inclusion, extracted data and assessed the risk of bias. We report results with 95% confidence intervals (CIs).Main resultsThis review includes eight studies with a total of 250 participants comparing nebuliser versus pMDI plus spacer treatment. We identified no studies comparing DPI with nebulisers. We found two studies assessing the primary outcome of 'change in forced expiratory volume in one second (FEV1) one hour after dosing'. We could not pool these studies, but both showed a non-significant difference in favour of the nebuliser group, with similar frequencies of serious adverse events. For the secondary outcome, 'change in FEV1 closest to one hour after dosing': we found a significant difference of 83 ml (95% CI 10 to 156, P = 0.03) in favour of nebuliser treatment. For the secondary outcome of adverse events, we found a non-significant odds ratio of 1.65 (95% CI 0.42 to 6.48) in favour of the pMDI plus spacer group.Authors' conclusionsThere is a lack of evidence in favour of one mode of delivery over another for bronchodilators during exacerbations of COPD. We found no difference between nebulisers versus pMDI plus spacer regarding the primary outcomes of FEV1 at one hour and safety. For the secondary outcome 'change in FEV1 closest to one hour after dosing' during an exacerbation of COPD, we found a greater improvement in FEV1 when treating with nebulisers than with pMDI plus spacers.A limited amount of data are available (eight studies involving 250 participants). These studies were difficult to pool, of low quality and did not provide enough evidence to favour one mode of delivery over another. No data of sufficient quality have been published comparing nebulisers versus DPIs in this setting. More studies are required to assess the optimal mode of delivery during exacerbations of COPD.

Bronchodilators are central to the management of chronic obstructive pulmonary disease (COPD). Clinical studies combining different classes of bronchodilators, in particular a long-acting muscarinic antagonist (LAMA) and a long-acting beta(2)-agonist (LABA), have demonstrated greater improvements in lung function (forced expiratory volume in 1 second, FEV1) in patients with COPD than monotherapy. FEV1 has served as an important diagnostic measurement of COPD, and the majority of clinical studies of currently available pharmacotherapies grade effectiveness of treatment regimens based on improvements in FEV1. However, FEV1 alone may not adequately reflect the overall health status of the patient. Published evidence suggests that LABA/LAMA combination therapies demonstrate greater improvements in patient-centred outcomes such as dyspnoea, symptoms, rescue medication use, and quality of life than individual drugs used alone. Evaluating patient-centred outcomes associated with COPD is likely to play an important role in future research as a measure of overall treatment effectiveness. Raising awareness of the importance of outcomes beyond lung function alone, particularly in primary care where most patients initially present themselves for medical evaluation, should form a fundamental part of a more holistic approach to COPD management. (C) 2012 Primary Care Respiratory Society UK. All rights reserved. T van der Molen and M Cazzola. Prim Care Respir J 2012; 21(1): 101-108 http://dx.doi.org/10.4104/pcrj.2011.00102

Background: A major goal in the management of chronic obstructive pulmonary disease (COPD) is to ensure that the burden of the disease for patients with COPD is limited and that patients will have the best possible quality of life.Aims: To explore all the possible factors that could influence disease-specific quality of life and health status in patients with COPD.Methods: A systematic review of the literature and a meta-analysis were performed to explore the factors that could have a positive or negative effect on quality of life and/or health status in patients with COPD.Results: Quality of life and health status are determined by certain factors included gender, disease severity indices, lung function parameters, body mass index, smoking, symptoms, co-morbidity, depression, anxiety, and exacerbations. Factors such as dyspnoea, depression, anxiety and exercise tolerance were found to be more correlated with health status than the widely used spirometric values. Forced expiratory volume in one second had a weak to modest Pearson weighted correlation coefficient which ranged from -0.110 to -0.510 depending on the questionnaire used.Conclusions: The broad range of determining factors suggests that, in order to reach the management goals, health status should be measured in addition to lung function in patients with COPD. (C) 2011 Primary Care Respiratory Society UK. All rights reserved. I Tsiligianni, et al. Prim Care Respir J 2011; 20(3): 257-268 http://dx.doi.org/10.4104/pcrj.2011.00029

Asthma and chronic obstructive pulmonary disease (COPD) show similarities and substantial differences. The Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental exposures (Postma and Boezen, Chest 2004; 126: 96S2104S). Thus, a particular group of shared genetic factors may lead to asthma when combined with specific environmental factors that are met at a certain stage in life, whereas combination with other environmental factors, or similar environmental factors at a different stage in life, will lead toward COPD. Multiple genes have been found for asthma and COPD. In addition to genes unique to these diseases, some shared genetic risk factors exist. Moreover, there are both common host risk factors and environmental risk factors for asthma and COPD. Here we put forward, based on the data available, that genes that affect lung development in utero and lung growth in early childhood in interaction with environmental detrimental stimuli, such as smoking and air pollution, are contributing to asthma in childhood and the ultimate development of COPD. Additional genes and environmental factors then drive specific immunological mechanisms underlying asthma, and others may contribute to the ultimate development of specific subtypes of COPD(i. e., airway disease with mucous hypersecretion, small airway disease, and emphysema). The genetic predisposition to the derailment of certain pathways may further help to define subgroups of asthma and COPD. In the end this may lead to stratification of patients by their genetic make-up and open new therapeutic prospects.

Contains fulltext : 95692.pdf (Publisher’s version ) (Open Access) BACKGROUND: Emphysema and small airway disease both contribute to chronic obstructive pulmonary disease (COPD), a disease characterised by accelerated decline in lung function. The association between the extent of emphysema in male current and former smokers and lung function decline was investigated. METHODS: Current and former heavy smokers participating in a lung cancer screening trial were recruited to the study and all underwent CT. Spirometry was performed at baseline and at 3-year follow-up. The 15th percentile (Perc15) was used to assess the severity of emphysema. RESULTS: 2085 men of mean age 59.8 years participated in the study. Mean (SD) baseline Perc15 was -934.9 (19.5) HU. A lower Perc15 value correlated with a lower forced expiratory volume in 1 s (FEV(1)) at baseline (r=0.12, p

Rationale: Although cigarette smoking is the most important cause of chronic obstructive pulmonary disease (COPD), a substantial proportion of COPD cases cannot be explained by smoking alone.Objectives: To evaluate the risk factors for COPD besides personal cigarette smoking.Methods: We constituted an ad hoc subcommittee of the American Thoracic Society Environmental and Occupational Health Assembly. An international group of members was invited, based on their scientific expertise in a specific risk factor for COPD. For each risk factor area, the committee reviewed the literature, summarized the evidence, and developed conclusions about the likelihood of it causing COPD. All conclusions were based on unanimous consensus.Measurements and Main Results: The population-attributable fraction for smoking as a cause of COPD ranged from 9.7 to 97.9%, but was less than 80% in most studies, indicating a substantial burden of disease attributable to nonsmoking risk factors. On the basis of our review, we concluded that specific genetic syndromes and occupational exposures were causally related to the development of COPD. Traffic and other outdoor pollution, secondhand smoke, biomass smoke, and dietary factors are associated with COPD, but sufficient criteria for causation were not met. Chronic asthma and tuberculosis are associated with irreversible loss of lung function, but there remains uncertainty about whether there are important phenotypic differences compared with COPD as it is typically encountered in clinical settings.Conclusions: In public health terms, a substantive burden of COPD is attributable to risk factors other than smoking. To prevent COPD-related disability and mortality, efforts must focus on prevention and cessation of exposure to smoking and these other, less well-recognized risk factors.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disorder with high mortality worldwide. Studies on the role of candidate genes and their polymorphisms in COPD development have so far produced ambiguous results.Objectives: The aim of this study was to reveal the role of COPD candidate genes using data collected in previous research.Methods: We performed meta-analyses on 20 polymorphisms in 12 genes, after searching the PubMed and Embase databases for publications on COPD. These genes involve three main pathways associated with COPD development: the inflammatory, protease-antiprotease balance, and antioxidant pathways.Measurements and Main Results: We obtained significant results for three TGFB1 polymorphisms, although these were based only on a few studies. The IL1RN VNTR polymorphism increases the risk for COPD (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.09-2.65), whereas the TNFA -308 G/A polymorphism does so only in Asian populations (OR, 2.01; 95% CI, 1.21-3.31). The GSTP1 I105V polymorphism was protective for COPD in Asian populations only (OR, 0.69; 95% Cl, 0.56-0.85).Conclusions: These results demonstrate the importance of ethnicity in identifying specific COPD genes.

Purpose: Update of a clinical practice guideline for the physiotherapy management of patients with chronic obstructive pulmonary disease supporting the clinical decision-making process.Methods: A systematic computerized literature search was performed on different modalities for improving physical exercise capacity, reducing exertional dyspnoea, improving airway clearance and encouraging changes in physical activity behaviour. Methodological quality was scored with the PEDro Scale. Scientific conclusions were graded according to the criteria of the `Dutch Evidence Based Guideline Development Platform'. These, together with practical considerations, were used to formulate recommendations for clinical practice.Results: A total of 103 studies were included in the systematic review, consisting of five meta-analyses of randomized controlled trials, 84 randomized controlled trials and 14 uncontrolled studies. Twenty scientific conclusions supported six recommendations on physical exercise training. Nineteen scientific conclusions supported eight recommendations on interventions for reducing dyspnoea. Five scientific conclusions supported seven recommendations concerning treatment modalities to improve mucus clearance, and two scientific conclusions supported two recommendations on strategies for encouraging permanent changes in physical activity behaviour.Conclusions: Strong recommendations support the use of physical exercise training to improve health-related quality of life and functional exercise capacity. Future research should investigate whether additional interventions for reducing exertional dyspnoea have a place as adjuncts to physical exercise training in selected patients. In addition, treatment of impaired mucus clearance, especially during acute exacerbations, requires further research. With the advance of new technologies for objective measurements of physical activities in daily life more research is needed concerning interventions to initiate and maintain physical activity behaviour change during and after supervised physical exercise training programmes

Severe asthma exacerbations are periods of intense airway inflammation that have been hypothesised to contribute to structural changes in the airways. If so, accelerated lung function decline over time should be more prevalent in adult patients with asthma who have frequent exacerbations than those without, but to date this has not been demonstrated.A cohort study was performed in order to investigate the effect of severe exacerbations on the progression of airway obstruction in 93 nonsmoking asthmatics with moderate-to-severe disease prior to treatment with inhaled corticosteroids. Subjects were followed for >= 5 yrs (median follow-up 11 yrs).In total, 56 (60.2%) subjects experienced at least one severe exacerbation (median rate 0.10.yr(-1)). Oral corticosteroid use and more severe airway obstruction at baseline were associated with a higher exacerbation rate. Independent of these variables, asthma patients with frequent exacerbations had a significantly larger annual decline in forced expiratory volume in one second (FEV1; median difference (95% confidence interval) 16.9 (1.5-32.2) mL.yr(-1)). Exacerbation rate significantly predicted an excess decline in FEV1, such that one severe exacerbation per year was associated with a 30.2 mL greater annual decline in FEV1.These data support the hypothesis that exacerbations, indicating intermittent periods of worsening airway inflammation, are associated with excess lung function decline in asthma.

Background The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification of severity of chronic obstructive pulmonary disease (COPD) is based solely on obstruction and does not capture physical functioning. The hypothesis that the Medical Research Council (MRC) dyspnoea scale would correlate better with quality of life than the level of airflow limitation was examined. Aim To study the associations between quality of life in smokers and limitations in physical functioning (MRC dyspnoea scale) and, quality of life and airflow limitation (GOLD COPD stages). Design Cross-sectional study. Setting The city of IJsselstein, a small town in the centre of The Netherlands. Method Male smokers aged 40-65 years without a prior diagnosis of COPD and enlisted with a general practice, participated in this study. Quality of life was assessed by means of a generic (SF-36) and a disease-specific, questionnaire (QOLRIQ). Results A total of 395 subjects (mean age 55.4 years, pack years 27.1) performed adequate spirometry and completed the questionnaires. Limitations of physical functioning according to the MRC dyspnoea scale were found in 25.1% (99/395) of the participants and airflow limitation in 40.2% (159/395). The correlations of limitations of physical functioning with all quality-of-life components were stronger than the correlations of all quality-of-life subscales with the severity of airflow limitation. Conclusion In middle-aged smokers the correlation of limitations of physical functioning (MRC dyspnoea scale) with quality of life was stronger than the correlation of the severity of airflow limitation with quality of life. Future staging systems of severity of COPD should capture this and not rely on forced expiratory volume in one second (FEV1) alone.

To determine inter-rater reliability of sarcoidosis-related computed tomography (CT) findings that can be used for scoring of thoracic sarcoidosis. CT images of 51 patients with sarcoidosis were scored by five chest radiologists for various abnormal CT findings (22 in total) encountered in thoracic sarcoidosis. Using intra-class correlation coefficient (ICC) analysis, inter-rater reliability was analysed and reported according to the Guidelines for Reporting Reliability and Agreement Studies (GRRAS) criteria. A pre-specified sub-analysis was performed to investigate the effect of training. Scoring was trained in a distinct set of 15 scans in which all abnormal CT findings were represented. Median age of the 51 patients (36 men, 70 %) was 43 years (range 26 – 64 years). All radiographic stages were present in this group. ICC ranged from 0.91 for honeycombing to 0.11 for nodular margin (sharp versus ill-defined). The ICC was above 0.60 in 13 of the 22 abnormal findings. Sub-analysis for the best-trained observers demonstrated an ICC improvement for all abnormal findings and values above 0.60 for 16 of the 22 abnormalities. In our cohort, reliability between raters was acceptable for 16 thoracic sarcoidosis-related abnormal CT findings. • Thoracic sarcoidosis is common; knowledge on reliability of CT scoring is limited. • Scoring CT abnormalities in pulmonary sarcoidosis can achieve good inter-rater agreement. • CT scoring validation in thoracic sarcoidosis is important for diagnostic and prognostic studies.

Another good year for biomarkers Identification of a systemic molecular signature facilitating early diagnosis and enabling targeted therapy is the Holy Grail for the investigators of many pulmonary diseases, particularly those with heterogeneous presentation such as chronic obstruction pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). Genome-wide gene expression profiling of large groups of patients has revealed a clear gene signature for elastogenesis during COPD and identified fibulin-5 as a potential molecular target.1 Genetic regulation of gene expression patterns was investigated by integrative genomics which identified cystatin C (CST3) and CD22 as causal genes for airflow obstruction.2 The fact that these gene expression patterns in COPD are dynamic during treatment, reflecting disease severity, highlights the potential of this approach for the development of molecular phenotype-driven therapy for COPD.3 Similarly, a coordinated approach was used to assess the relationship between gene expression patterns, pathological features and systemic biomarkers to identify indicators of disease severity in patients with IPF. MMP3 and CXCL13 emerged as systemic biomarkers that reflect brochiolisation and lymphoid aggregates and are predicted to be of clinical value as prognostic or surrogate markers of disease severity in these patients.4 An alternative method of predicting cancer risk in patients presenting with endobronchial squamous metaplasia is the identification of DNA copy number aberration. This technique has proved a highly accurate biomarker for assessment of disease progression and could assist in deciding which patients with endobronchial lesions may benefit from more aggressive treatment or closer surveillance.5 ### Smoking and steroids Further evidence that smoking is bad for you—and your immune system—stems from a series of papers examining the effect of cigarette smoke on innate immune function. Tobacco smoke blunted secretion of key innate cytokines such as interferon γ and tumour necrosis factor α and impaired the ability of macrophages derived from peripheral blood or the airways to …

Background: Symptom-based questionnaires may enhance chronic obstructive pulmonary disease (COPD) screening in primary care. Objectives: We prospectively tested questions to help identify COPD among smokers without prior history of lung disease. Methods: Subjects were recruited via random mailing to primary care practices in Aberdeen, UK, and Denver, Colo., USA. Current and former smokers aged 40 or older with no prior respiratory diagnosis and no respiratory medications in the past year were enrolled. Participants answered questions covering demographics and symptoms and then underwent spirometry with reversibility testing. A study diagnosis of COPD was defined as fixed airway obstruction as measured by postbronchodilator FEV1/FVC Results: 818 subjects completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analysis, which was reduced to 17 items for entry into multivariate regression. Eight items had significant relationships with the study diagnosis of COPD, including age, pack-years, body mass index, weather-affected cough, phlegm without a cold, morning phlegm, wheeze frequency, and history of any allergies. Individual items yielded odds ratios ranging from 0.23 to 12. This questionnaire demonstrated a sensitivity of 80.4 and specificity of 72.0. Conclusions: A simple patient self-administered questionnaire can be used to identify patients with a high likelihood of having COPD, for whom spirometric testing is particularly important. Implementation of this questionnaire could enhance the efficiency and diagnostic accuracy of current screening efforts.

Introduction: beta-Blockers are known to worsen FEV1 and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment. Design: A double-blind, placebo-controlled, randomized, cross-over study. Setting: An ambulatory, hospital outpatient clinic of pulmonary diseases. Patients: Patients with mild-to-moderate irreversible COPD and AHR. Intervention: Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period >= 3 days. On day 4 of treatment, FEV1 and PC20 were assessed. Immediately hereafter, formoterol (12 mu g) was administered and FEV1 was measured for up to 30 min. Results: PC20 was significantly lower (p

Background: Childhood asthma is generally believed to be a disorder with a good prognosis. However, some asthmatics develop irreversible airway obstruction, probably as a result of airway remodelling. Methods: After 21-33 years, 228 adults (aged 13-44 years at baseline) with a history of asthma were re-examined to assess risk factors for the development of irreversible airway obstruction (IAO, forced expiratory volume in 1 second (FEV1) Results: At follow up, 41% did not have airway obstruction (NAO), 43% had reversible airway obstruction (RAO), and 16% had IAO; 23% had a reduced transfer coefficient. Patients with RAO had asthma-like characteristics (wheezing, asthma attacks, bronchial hyperresponsiveness (BHR)) while patients with IAO had COPD-like symptoms (cough, phlegm, dyspnoea) at follow up. The development of IAO is determined by a lower FEV1, less reversibility of airway obstruction and, surprisingly, less severe BHR at initial screening. Eighty percent of the patients with asthma who used anti-inflammatory medication still had airway obstruction, but IAO developed less frequently. Smoking was associated with a reduced transfer coefficient but not with the development of IAO. Female sex was associated with a reduced transfer coefficient, whereas corticosteroid use was not. Conclusions: Although IAO and a low transfer coefficient are both characteristics of COPD, they represent distinct entities in adult asthmatics in terms of symptomatology, aetiology, and probably in therapeutic approaches and disease prevention.