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1.  Absence of Pneumocystis jirovecii Colonization in Human Immunodeficiency Virus-Infected Individuals With and Without Airway Obstruction and With Undetectable Viral Load 
Open Forum Infectious Diseases  2016;3(1):ofw044.
Pneumocystis jirovecii colonization has been associated with non-acquired immune deficiency syndrome (AIDS) pulmonary comorbidity. We used spirometry to measure pulmonary function and analyzed oral wash specimens by quantitative polymerase chain reaction (PCR), targeting the large mitochondrial ribosomal subunit. For sensitivity control, a blinded subsample was subjected to touch-down PCRs, targeting both large and small ribosomal subunits and the major surface glycoprotein. Pneumocystis jirovecii deoxyribonucleic acid (DNA) was detected in 1 of 156 (95% confidence interval, .1%–3.5%) virologically suppressed human immunodeficiency virus (HIV)-infected individuals confirmed by all PCR methods. Thus, prevalence of P jirovecii colonization was low and unlikely to be a major cause of pulmonary comorbidity in this group of well treated HIV-infected individuals.
doi:10.1093/ofid/ofw044
PMCID: PMC4800465  PMID: 27006967
airway obstruction; HIV-1; Pneumocystis; colonization
3.  Low Use and Adherence to Maintenance Medication in Chronic Obstructive Pulmonary Disease in the General Population 
ABSTRACT
OBJECTIVE
We tested the hypothesis that use of and adherence to maintenance medication is low among in-dividuals in the general population who have chronic obstructive pulmonary disease (COPD) , even in cases of severe and very severe COPD.
DESIGN AND PARTICIPANTS
We identified 5,812 individuals with COPD from the Copenhagen General Population Study, and classified them according to the Global Initiative for Obstructive Lung Disease (GOLD) airflow limitation grades 1–4. Dispensing of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, long-acting anti-cholinergics, or long-acting beta2-agonists was identified in a nationwide registry. Use of medication was defined as medication dispensed during a one-year period , and adherence was calculated from dosages available in one year.
KEY RESULTS
Use of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists varied from 2 % to 61 % (p < 0.001, test for trend), long-acting anti-cholinergics varied from 0.4 % to 36 % (p < 0.001), and long-acting beta2-agonists varied from 0.3 % to 11 % (p < 0.001. Among utilizers of these medications, adherence varied from 29 % to 56 % (p < 0.001, test for trend) across GOLD 1–4 for fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, from 51 % to 68 % (p = 0.11) for long-acting anti-cholinergics, and from 25 to 62 % (p = 0.01) for long-acting beta2-agonists.
CONCLUSIONS
Use of and adherence to maintenance medication for COPD in the general population was associated with the severity of COPD as defined by GOLD, but even in severe and very severe COPD, use and adherence was low.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-014-3029-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-014-3029-0
PMCID: PMC4284264  PMID: 25245885
COPD; severity; GOLD; long-acting medication
4.  The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in asthma 
BMC Pulmonary Medicine  2015;15:160.
Background
Novel therapies need to be evaluated in normal clinical practice to allow a true representation of the treatment effectiveness in real-world settings.
Methods/design
The Salford Lung Study is a pragmatic randomised controlled trial in adult asthma, evaluating the clinical effectiveness and safety of once-daily fluticasone furoate (100 μg or 200 μg)/vilanterol 25 μg in a novel dry-powder inhaler, versus existing asthma maintenance therapy. The study was initiated before this investigational treatment was licensed and conducted in real-world clinical practice to consider adherence, co-morbidities, polypharmacy, and real-world factors. Primary endpoint: Asthma Control Test at week 24; safety endpoints include the incidence of serious pneumonias. The study utilises the Salford electronic medical record, which allows near to real-time collection and monitoring of safety data.
Discussion
The Salford Lung Study is the world’s first pragmatic randomised controlled trial of a pre-licensed medication in asthma. Use of patients’ linked electronic health records to collect clinical endpoints offers minimal disruption to patients and investigators, and also ensures patient safety. This highly innovative study will complement standard double-blind randomised controlled trials in order to improve our understanding of the risk/benefit profile of fluticasone furoate/vilanterol in patients with asthma in real-world settings.
Trial registration
Clinicaltrials.gov, NCT01706198; 04 October 2012.
doi:10.1186/s12890-015-0150-8
PMCID: PMC4676141  PMID: 26651333
Asthma; Electronic medical record; Fluticasone furoate/vilanterol; Inhaled corticosteroid/long-acting β2-agonist; Pragmatic randomised controlled trial; Real-world evidence
5.  Common Genetic Variants Associated with Resting Oxygenation in Chronic Obstructive Pulmonary Disease 
Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10−5) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10−8). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.
doi:10.1165/rcmb.2014-0135OC
PMCID: PMC4224086  PMID: 24825563
chronic obstructive pulmonary disease; hypoxemia; pulse oximetry; genome-wide association study; oxygen saturation
6.  The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in chronic obstructive pulmonary disease 
Respiratory Research  2015;16(1):101.
Background
New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy.
Methods
Patients with chronic obstructive pulmonary disease (COPD), ≥40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data.
Conclusions
The Salford Lung Study is the world’s first pragmatic randomised controlled trial of a pre-licensed medication in COPD.
Trial registration
Clinicaltrials.gov identifier NCT01551758.
doi:10.1186/s12931-015-0267-6
PMCID: PMC4558879  PMID: 26337978
7.  Systematic literature review of patient-reported outcome measures used in assessment and measurement of sleep disorders in chronic obstructive pulmonary disease 
Background
Sleep problems are common in patients with chronic obstructive pulmonary disease (COPD), but the validity of patient-reported outcome measures (PROMs) that measure sleep dysfunction has not been evaluated. We have reviewed the literature to identify disease-specific and non-disease-specific sleep PROMs that have been validated for use in COPD patients. The review also examined the psychometric properties of identified sleep outcome measures and extracted point and variability estimates of sleep instruments used in COPD studies.
Methods
The online EMBASE, MEDLINE, PsycINFO, and SCOPUS databases for all years to May 2014 were used to source articles for the review. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Criteria from the Medical Outcomes Trust Scientific Advisory Committee guidelines were used to evaluate the psychometric properties of all sleep PROMs identified.
Results
One COPD-specific and six non-COPD-specific sleep outcome measures were identified and 44 papers met the review selection criteria. We only identified one instrument, the COPD and Asthma Sleep Impact Scale, which was developed specifically for use in COPD populations. Ninety percent of the identified studies used one of two non-disease-specific sleep scales, ie, the Pittsburgh Sleep Quality Index and/or the Epworth Sleep Scale, although neither has been tested for reliability or validity in people with COPD.
Conclusion
The results highlight a need for existing non-disease-specific instruments to be validated in COPD populations and also a need for new disease-specific measures to assess the impact of sleep problems in COPD.
doi:10.2147/COPD.S68093
PMCID: PMC4330032  PMID: 25709424
sleep; symptom assessment; chronic obstructive pulmonary disease; systematic review
8.  Surfactant protein D, Club cell protein 16, Pulmonary and activation-regulated chemokine, C-reactive protein, and Fibrinogen biomarker variation in chronic obstructive lung disease 
Respiratory Research  2014;15(1):147.
Chronic obstructive pulmonary disease (COPD) is a multifaceted condition that cannot be fully described by the severity of airway obstruction. The limitations of spirometry and clinical history have prompted researchers to investigate a multitude of surrogate biomarkers of disease for the assessment of patients, prediction of risk, and guidance of treatment. The aim of this review is to provide a comprehensive summary of observations for a selection of recently investigated pulmonary inflammatory biomarkers (Surfactant protein D (SP-D), Club cell protein 16 (CC-16), and Pulmonary and activation-regulated chemokine (PARC/CCL-18)) and systemic inflammatory biomarkers (C-reactive protein (CRP) and fibrinogen) with COPD. The relevance of these biomarkers for COPD is discussed in terms of their biological plausibility, their independent association to disease and hard clinical outcomes, their modification by interventions, and whether changes in clinical outcomes are reflected by changes in the biomarker.
doi:10.1186/s12931-014-0147-5
PMCID: PMC4256818  PMID: 25425298
COPD; Biomarker; SP-D; CC-16; PARC/CCL-18; CRP; Fibrinogen
9.  Are patients with COPD treated with NIV in accordance with national guidelines? An internal audit 
European Clinical Respiratory Journal  2014;1:10.3402/ecrj.v1.24506.
Introduction
Non-invasive ventilation (NIV) as an add-on modality to medical treatment has been recommended in national guidelines for patients acutely admitted with chronic obstructive pulmonary disorder (COPD) exacerbation and hypercapnic respiratory failure. To address concerns regarding whether NIV is used appropriately, we conducted an audit of COPD patients admitted to a university hospital in Denmark.
Material and methods
Data from medical records were retrieved for two cohorts in 2010: 1) all patients admitted to the Medical Emergency Ward with the diagnosis of COPD, and 2) all patients receiving NIV regardless of their diagnosis at the Respiratory Ward. Demographic data and outcome of treatment were registered.
Results
Cohort 1 comprised 804 admissions fulfilling criteria for COPD at evaluation, and of the 804 admissions, NIV was initiated in 151 (18.7%) admissions. In 42 additional cases (5.2%), initial mild respiratory acidosis was registered at admission, fulfilling criteria for NIV treatment; and, in 36 cases, the clinical status was reported as improved or not reported at all; no deaths were observed. In cohort 2, 124 admissions were registered that comprised 110 admissions with COPD and 14 without a diagnosis of COPD (of which half had a ‘not-to-intubate’ order). The indication for NIV treatment was met in 92.7% of the COPD admissions.
Conclusion
NIV was initiated in 18.8% of the COPD admissions, and in an additional 5.2%, NIV criteria were met without initiation. In 82.3% of the admissions receiving NIV, a COPD diagnosis and correct criteria for NIV treatment were met.
doi:10.3402/ecrj.v1.24506
PMCID: PMC4629757  PMID: 26557243
non-invasive ventilation; respiratory failure; COPD; hypercapnea
10.  Increased levels of soluble interleukin-6 receptor and CCL3 in COPD sputum 
Respiratory Research  2014;15(1):103.
Background
COPD patients have increased numbers of macrophages and neutrophils in the lungs. Interleukin-6 (IL-6) trans-signaling via its soluble receptor sIL-6R, governs the influx of innate immune cells to inflammatory foci through regulation of the chemokine CCL3. We hypothesized that there would be enhanced levels of IL-6, sIL-6R and CCL3 in COPD sputum.
Methods
59 COPD patients, 15 HNS and 15 S underwent sputum induction and processing with phosphate buffered saline to obtain supernatants for IL-6, sIL-6R and CCL3 analysis. Cytoslides were produced for differential cell counting and immunocytochemistry (COPD; n = 3) to determine cell type surface expression of the CCL3 receptors CCR5 and CCR1.
Results
COPD patients expressed higher levels (p < 0.05) of sIL-6R and CCL3 compared to controls (sIL-6R medians pg/ml: COPD 166.4 vs S 101.1 vs HNS 96.4; CCL3 medians pg/ml: COPD 117.9 vs S 0 vs HNS 2.7). COPD sIL-6R levels were significantly correlated with sputum neutrophil (r = 0.5, p < 0.0001) and macrophage (r = 0.3, p = 0.01) counts. Immunocytochemical analysis revealed that CCR5 and CCR1 were exclusively expressed on airway macrophages.
Conclusion
Enhanced airway generation of sIL-6R may promote IL-6 trans-signaling in COPD. Associated upregulation of CCL3 may facilitate the recruitment of macrophages into the airways by ligation of CCR1 and CCR5.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0103-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12931-014-0103-4
PMCID: PMC4156958  PMID: 25183374
COPD; Sputum; Two-step sputum processing; Interleukin-6; sIL-6R; CCL3
11.  Extrafine Beclomethasone/formoterol compared to Fluticasone/salmeterol Combination Therapy in COPD 
Background
The study evaluated the efficacy of beclomethasone dipropionate/formoterol fumarate (BDP/FF) extrafine combination versus fluticasone propionate/salmeterol (FP/S) combination in COPD patients.
Methods
The trial was a 12-week multicentre, randomised, double-blind, double dummy study; 419 patients with moderate/severe COPD were randomised to BDP/FF 200/12 μg or FP/S 500/50 μg twice daily. The primary objective was to demonstrate the equivalence between treatments in terms of Transition Dyspnoea Index (TDI) score and the superiority of BDP/FF in terms of change from pre-dose in the first 30 minutes in forced expiratory volume in the first second (FEV1). Secondary endpoints included lung function, symptom scores, symptom-free days and use of rescue medication, St. George’s Respiratory Questionnaire, six minute walking test and COPD exacerbations.
Results
BDP/FF was equivalent to FP/S in terms of TDI score and superior in terms of FEV1 change from pre-dose (p < 0.001). There were no significant differences between treatments in secondary outcome measures, confirming overall comparability in terms of efficacy and tolerability. Moreover, a clinically relevant improvement (>4 units) in SGRQ was detected in the BDP/FF group only.
Conclusion
BDP/FF extrafine combination provides COPD patients with an equivalent improvement of dyspnoea and a faster bronchodilation in comparison to FP/S.
Trial registration
ClinicalTrials.gov: NCT01245569
doi:10.1186/1471-2466-14-43
PMCID: PMC4008134  PMID: 24621109
12.  Prognostic Value of C-Reactive Protein, Leukocytes, and Vitamin D in Severe Chronic Obstructive Pulmonary Disease 
The Scientific World Journal  2014;2014:140736.
Inflammatory biomarkers predict mortality and hospitalisation in chronic obstructive pulmonary disease (COPD). Yet, it remains uncertain if biomarkers in addition to reflecting disease severity add new prognostic information on severe COPD. We investigated if leukocytes, C-reactive protein (CRP), and vitamin D were independent predictors of mortality and hospitalisation after adjusting for disease severity with an integrative index, the i-BODE index. In total, 423 patients participating in a pulmonary rehabilitation programme, with a mean value of FEV1 of 38% of predicted, were included. Mean followup was 45 months. During the follow-up period, 149 deaths (35%) were observed and 330 patients (78.0%) had at least one acute hospitalisation; 244 patients (57.7%) had at least one hospitalisation due to an exacerbation of COPD. In the analysis (Cox proportional hazards model) fully adjusted for age, sex, and i-BODE index, the hazard ratio for 1 mg/L increase in CRP was 1.02 (P = 0.003) and for 1 × 109/L increase in leukocytes was 1.43 (P = 0.03). Only leukocyte count was significantly associated with hospitalisation. Vitamin D was neither associated with mortality nor hospitalisation. Leukocytes and CRP add little information on prognosis and vitamin D does not seem to be a useful biomarker in severe COPD in a clinical setting.
doi:10.1155/2014/140736
PMCID: PMC3918710  PMID: 24587707
13.  Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease 
Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility.
Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD.
Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated.
Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts.
Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility.
Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
doi:10.1164/rccm.201206-1013OC
PMCID: PMC3622441  PMID: 23144326
biomarker; chronic obstructive pulmonary disease; genome-wide association study
14.  Localization of Microfibrillar-Associated Protein 4 (MFAP4) in Human Tissues: Clinical Evaluation of Serum MFAP4 and Its Association with Various Cardiovascular Conditions 
PLoS ONE  2013;8(12):e82243.
Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease.
doi:10.1371/journal.pone.0082243
PMCID: PMC3862580  PMID: 24349233
15.  Enzyme-Linked Immunosorbent Assay Characterization of Basal Variation and Heritability of Systemic Microfibrillar-Associated Protein 4 
PLoS ONE  2013;8(12):e82383.
Background
Microfibrillar-associated protein 4 (MFAP4) is a systemic biomarker that is significantly elevated in samples from patients suffering from hepatic cirrhosis. The protein is generally localized to elastic fibers and other connective tissue fibers in the extracellular matrix (ECM), and variation in systemic MFAP4 (sMFAP4) has the potential to reflect diverse diseases with increased ECM turnover. Here, we aimed to validate an enzyme-linked immunosorbent assay (ELISA) for the measurement of sMFAP4 with an emphasis on the robustness of the assay. Moreover, we aimed to determine confounders influencing the basal sMFAP4 variability and the genetic contribution to the basal variation.
Methods
The sandwich ELISA was based on two monoclonal anti-MFAP4 antibodies and was optimized and calibrated with a standard of recombinant MFAP4. The importance of pre-analytical sample handling was evaluated regarding sample tube type, time, and temperature conditions. The mean value structure and variance structure was determined in a twin cohort including 1,417 Danish twins (age 18-67 years) by mixed-effect linear regression modeling.
Results
The practical working range of the sandwich ELISA was estimated to be 4-75 U/ml. The maximum intra- and inter-assay variation was estimated to be 8.7% and 6.6%, respectively. Sample handling and processing appeared to influence MFAP4 measurements only marginally. The average concentration of sMFAP4 in the serum was 18.9 ± 8.4 (SD) U/ml in the twin cohort (95% CI: 18.5-19.4, median sMFAP4 17.3 U/ml). The mean structure model was demonstrated to include waist-hip ratio, age, and cigarette smoking status in interactions with gender. A relatively low heritability of h2 = 0.24 was found after applying a model including additive genetic factors and shared and non-shared environmental factors.
Conclusions
The described ELISA provides robust measures of the liver fibrosis marker sMFAP4. The low heritability and the relatively limited basal variation suggest that increased sMFAP4 reflects disease-induced processes.
doi:10.1371/journal.pone.0082383
PMCID: PMC3853316  PMID: 24324779
16.  A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13 
Human Molecular Genetics  2011;21(4):947-957.
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
doi:10.1093/hmg/ddr524
PMCID: PMC3298111  PMID: 22080838
17.  GOLD and the fixed ratio 
doi:10.2147/COPD.S35769
PMCID: PMC3459655  PMID: 23049251
18.  Examining fatigue in COPD: development, validity and reliability of a modified version of FACIT-F scale 
Introduction
Fatigue is a disruptive symptom that inhibits normal functional performance of COPD patients in daily activities. The availability of a short, simple, reliable and valid scale would improve assessment of the characteristics and influence of fatigue in COPD.
Methods
At baseline, 2107 COPD patients from the ECLIPSE cohort completed the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scale. We used well-structured classic method, the principal components analysis (PCA) and Rasch analysis for structurally examining the 13-item FACIT-F.
Results
Four items were less able to capture fatigue characteristics in COPD and were deleted. PCA was applied to the remaining 9 items of the modified FACIT-F and resulted in three interpretable dimensions: i) general (5 items); ii) functional ability (2 items); and iii) psychosocial fatigue (2 items). The modified FACIT-F had high internal consistency (Cronbach's α = 0.91) and it did not fit a uni-dimensional Rasch model, confirming the prior output from the PCA. The correlations between total score and each dimension were ≥ 0.64 and within dimensions ≥0.43 (p < 0.001 for all).
The original and modified FACIT-F had significant convergent validity; its scores were associated with SGRQ total score (0.69 and 0.7) and mMRC dyspnoea scores (0.48 and 0.47), (p = <0.001 for all). The scale had meaningful discriminating ability in identifying patients with poor exercise performance and more depressive symptoms.
Conclusion
The original and modified FACIT-F are valid and reliable scales in COPD. The modified version is shorter and measures not only total fatigue but also its sub-components in COPD.
doi:10.1186/1477-7525-10-100
PMCID: PMC3491053  PMID: 22913289
Chronic obstructive pulmonary disease; Fatigue; Exercise capacity; Health status
19.  Persistent Systemic Inflammation is Associated with Poor Clinical Outcomes in COPD: A Novel Phenotype 
PLoS ONE  2012;7(5):e37483.
Background
Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).
Methods and Findings
Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.
Conclusions
Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.
doi:10.1371/journal.pone.0037483
PMCID: PMC3356313  PMID: 22624038
20.  The Impact of Nonlinear Smoking Effects on the Identification of Gene-by-Smoking Interactions in COPD Genetics Studies 
Thorax  2010;66(10):903-909.
Background
The identification of gene-by-environment interactions is important to understand the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and FEV1; however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.
Methods
We examined the relationship between FEV1 and pack-years of smoking exposure in 4 large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, we compared the accuracy and power of two different approaches to model smoking by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.
Results
We identified nonlinear relationships between smoking and FEV1 in 4 large cohorts. We demonstrated that in most situations where the relationship between pack-years and FEV1 is nonlinear, a piecewise-linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. We applied the piecewise linear approach to a genetic association analysis of the PI*Z allele in the Norway case-control cohort and identified a potential PI*Z-by-smoking interaction (p=0.03 for FEV1 analysis, p= 0.01 for COPD susceptibility analysis).
Conclusion
In study samples with subjects having a wide range of COPD severity, a nonlinear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this nonlinearity can be more powerful and less-biased than the commonly-used approach of using total pack-years to model the smoking effect.
doi:10.1136/thx.2010.146118
PMCID: PMC3312798  PMID: 21163806
smoking; FEV1; gene-by-environment interaction; COPD; gene
21.  Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene 
Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.
Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.
Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.
Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10−5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.
Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
doi:10.1164/rccm.200910-1586OC
PMCID: PMC2937234  PMID: 20463177
emphysema; genetic linkage; metaanalysis; single nucleotide polymorphism
22.  Health status in the TORCH study of COPD: treatment efficacy and other determinants of change 
Respiratory Research  2011;12(1):71.
Background
Little is known about factors that determine health status decline in clinical trials of COPD.
Objectives
To examine health status changes over 3 years in the TORCH study of salmeterol+fluticasone propionate (SFC) vs. salmeterol alone, fluticasone propionate alone or placebo.
Methods
St George's Respiratory Questionnaire (SGRQ) was administered at baseline then every 6 months.
Measurements and Main Results
Data from 4951 patients in 28 countries were available. SFC produced significant improvements over placebo in all three SGRQ domains during the study: (Symptoms -3.6 [95% CI -4.8, -2.4], Activity -2.8 [95% CI -3.9, -1.6], Impacts -3.2 [95% CI -4.3, -2.1]) but the pattern of change over time differed between domains. SGRQ deteriorated faster in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III & IV relative to GOLD stage II (p < 0.001). There was no difference in the relationship between deterioration in SGRQ Total score and forced expiratory volume in one second (FEV1) decline (as % predicted) in men and women. Significantly faster deterioration in Total score relative to FEV1 % predicted was seen in older patients (≥ 65 years) and there was an age-related change in Total score that was independent of change in FEV1. The relationship between deterioration in FEV1 and SGRQ did not differ in different world regions, but patients in Asia-Pacific showed a large improvement in score that was unrelated to FEV1 change.
Conclusions
In addition to treatment effects, health status changes in clinical trials may be influenced by demographic and disease-related factors. Deterioration in health status appears to be fastest in older persons and those with severe airflow limitation.
Trial Registration
ClinicalTrials.gov: NCT00268216
doi:10.1186/1465-9921-12-71
PMCID: PMC3117702  PMID: 21627828
COPD; quality of life; health status; lung function
24.  Biomarkers of systemic inflammation and depression and fatigue in moderate clinically stable COPD 
Respiratory Research  2011;12(1):3.
Introduction
COPD is an inflammatory disease with major co-morbidities. It has recently been suggested that depression may be the result of systemic inflammation. We aimed to explore the association between systemic inflammation and symptoms of depression and fatigue in patients with mainly moderate and clinically stable COPD using a range of inflammatory biomarkers, 2 depression and 2 fatigue scales.
Method
We assessed 120 patients with moderate COPD (FEV1% 52, men 62%, age 66). Depression was assessed using the BASDEC and CES-D scales. Fatigue was assessed using the Manchester COPD-fatigue scale (MCFS) and the Borg scale before and after 6MWT. We measured systemic TNF-α, CRP, TNF-α-R1, TNF-α-R2 and IL-6.
Results
A multivariate linear model of all biomarkers showed that TNF-α only had a positive correlation with BASDEC depression score (p = 0.007). TNF-α remained positively correlated with depression (p = 0.024) after further adjusting for TNF-α-R1, TNF-α-R2, 6MWD, FEV1%, and pack-years. Even after adding the MCFS score, body mass and body composition to the model TNF-α was still associated with the BASDEC score (p = 0.044). Furthermore, patients with higher TNF-α level (> 3 pg/ml, n = 7) had higher mean CES-D depression score than the rest of the sample (p = 0.03). Borg fatigue score at baseline were weakly correlated with TNF-α and CRP, and with TNF-α only after 6MWT. Patients with higher TNF-α had more fatigue after 6MWD (p = 0.054).
Conclusion
This study indicates a possible association between TNF-α and two frequent and major co-morbidities in COPD; i.e., depression and fatigue.
doi:10.1186/1465-9921-12-3
PMCID: PMC3024938  PMID: 21208443
25.  Characterisation of COPD heterogeneity in the ECLIPSE cohort 
Respiratory Research  2010;11(1):122.
Background
Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).
Methods
We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.
Results
COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified.
Conclusions
The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.
doi:10.1186/1465-9921-11-122
PMCID: PMC2944278  PMID: 20831787

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