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1.  Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity 
PLoS ONE  2012;7(6):e38629.
The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r  =  −0.52, p  = 0.005 and r  =  −0.61, p  = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  −0.25, p  = 0.47 and r  =  −0.15, p  = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.
PMCID: PMC3373533  PMID: 22701684
2.  Identification of Clinical Phenotypes Using Cluster Analyses in COPD Patients with Multiple Comorbidities 
BioMed Research International  2014;2014:420134.
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, the severity of which is assessed using forced expiratory volume in 1 sec (FEV1, % predicted). Cohort studies have confirmed that COPD patients with similar levels of airflow limitation showed marked heterogeneity in clinical manifestations and outcomes. Chronic coexisting diseases, also called comorbidities, are highly prevalent in COPD patients and likely contribute to this heterogeneity. In recent years, investigators have used innovative statistical methods (e.g., cluster analyses) to examine the hypothesis that subgroups of COPD patients sharing clinically relevant characteristics (phenotypes) can be identified. The objectives of the present paper are to review recent studies that have used cluster analyses for defining phenotypes in observational cohorts of COPD patients. Strengths and weaknesses of these statistical approaches are briefly described. Description of the phenotypes that were reasonably reproducible across studies and received prospective validation in at least one study is provided, with a special focus on differences in age and comorbidities (including cardiovascular diseases). Finally, gaps in current knowledge are described, leading to proposals for future studies.
PMCID: PMC3934315
3.  The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2009;4(8):e6865.
Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD.
Methodology/Principal Findings
Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status.
Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.
PMCID: PMC2730536  PMID: 19718453
4.  Effect of bronchodilatation on single breath pulmonary uptake of carbon monoxide in chronic obstructive pulmonary disease 
We studied 21 COPD patients in stable clinical conditions to evaluate whether changes in lung function induced by cumulative doses of salbutamol alter diffusing capacity for carbon monoxide (DLCO), and whether this relates to the extent of emphysema as assessed by high resolution computed tomography (HRCT) quantitative analysis. Spirometry and DLCO were measured before and after cumulative doses of inhaled salbutamol (from 200 μg to 1000 μg). Salbutamol caused significant increments of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and flows at 30% of control FVC taken from both partial and maximal forced expiratory maneuvers. Functional residual capacity and residual volume were reduced, while total lung capacity did not change significantly. DLCO increased progressively with the incremental doses of salbutamol, but this became significant only at the highest dose (1000 μg) and was independent of the extent of emphysema, as assessed by radiological parameters. No significant changes were observed in CO transfer factor (DLCO/VA) and alveolar volume (VA). The results suggest that changes in lung function induced by cumulative doses of inhaled salbutamol are associated with a slight but significant increase in DLCO irrespective of the presence and extent of emphysema.
PMCID: PMC2707804  PMID: 18044104
lung volumes; high resolution computed tomography; chronic obstructive bronchitis; emphysema
5.  A new staging strategy for chronic obstructive pulmonary disease 
The best method for expressing lung function impairment is undecided. We tested in a population of patients with chronic obstructive pulmonary disease (COPD) whether forced expiratory volume in 1 second (FEV1) or FEV1 divided by height squared (FEV1/ht2) was better than FEV1 percent predicted (FEV1PP) for predicting survival.
FEV1, FEV1PP, and FEV1/ht2 recorded post bronchodilator were compared as predictors of survival in 1095 COPD patients followed for 15 years. A staging system for severity of COPD was defined from FEV1/ht2 and compared with the Global Initiative for Obstructive Lung Disease (GOLD) staging system.
FEV1/ht2 was a better univariate predictor of survival in COPD than FEV1 and both were better than FEV1PP. The best multivariate model for predicting survival included FEV1/ht2, age and sex. Comparing the GOLD stages with the FEV1/ht2 groups found that survival was more coherent within each FEV1/ht group than it was within each GOLD stage. FEV1/ht2 had 60% more people in its most severe group than the severest GOLD stage with these extra subjects having equivalently poor survival and had 155% more in the least severe group with equivalent survival. GOLD staging misclassified 51% of subjects with regard to survival.
We conclude that GOLD criteria using FEV1PP do not optimally stage COPD with regard to survival. An alternative strategy using FEV1/ht2 improves the staging of this disease. Studies which stratify COPD patients to determine the effect of interventions such as drug trials, rehabilitation, or management guidelines should consider alternatives to the GOLD classification.
PMCID: PMC2699963  PMID: 18268941
chronic obstructive pulmonary disease; spirometry; respiratory function tests
6.  Lung microbiology and exacerbations in COPD 
Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory condition in adults and is characterized by progressive airflow limitation that is not fully reversible. The main etiological agents linked with COPD are cigarette smoking and biomass exposure but respiratory infection is believed to play a major role in the pathogenesis of both stable COPD and in acute exacerbations. Acute exacerbations are associated with more rapid decline in lung function and impaired quality of life and are the major causes of morbidity and mortality in COPD. Preventing exacerbations is a major therapeutic goal but currently available treatments for exacerbations are not very effective. Historically, bacteria were considered the main infective cause of exacerbations but with the development of new diagnostic techniques, respiratory viruses are also frequently detected in COPD exacerbations. This article aims to provide a state-of-the art review of current knowledge regarding the role of infection in COPD, highlight the areas of ongoing debate and controversy, and outline emerging technologies and therapies that will influence future diagnostic and therapeutic pathways in COPD.
PMCID: PMC3437812  PMID: 22969296
COPD; exacerbations; bacteria; viruses
7.  Wood Smoke Exposure and Gene Promoter Methylation Are Associated with Increased Risk for COPD in Smokers 
Rationale: Wood smoke–associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.
Objectives: Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.
Methods: For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV1, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.
Measurements and Main Results: Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV1 (point estimate [± SE] −0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52–2.52 and 1.64 (95% confidence interval, 1.31–2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV1.
Conclusions: These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.
PMCID: PMC3001253  PMID: 20595226
wood smoke; cigarette smokers; airflow obstruction; gene promoter methylation in sputum DNA
8.  BODE index versus GOLD classification for explaining anxious and depressive symptoms in patients with COPD – a cross-sectional study 
Respiratory Research  2009;10(1):1.
Anxiety and depression are common and treatable risk factors for re-hospitalisation and death in patients with COPD. The degree of lung function impairment does not sufficiently explain anxiety and depression. The BODE index allows a functional classification of COPD beyond FEV1. The aim of this cross-sectional study was (1) to test whether the BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms; and (2) to assess which components of the BODE index are associated with these psychological aspects of COPD.
COPD was classified according to the GOLD stages based on FEV1%predicted in 122 stable patients with COPD. An additional four stage classification was constructed based on the quartiles of the BODE index. The hospital anxiety and depression scale was used to assess anxious and depressive symptoms.
The overall prevalence of anxious and depressive symptoms was 49% and 52%, respectively. The prevalence of anxious symptoms increased with increasing BODE stages but not with increasing GOLD stages. The prevalence of depressive symptoms increased with both increasing GOLD and BODE stages. The BODE index was superior to FEV1%predicted for explaining anxious and depressive symptoms. Anxious symptoms were explained by dyspnoea. Depressive symptoms were explained by both dyspnoea and reduced exercise capacity.
The BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms in COPD patients. These psychological consequences of the disease may play a role in future classification systems of COPD.
PMCID: PMC2626579  PMID: 19134192
9.  Lung Function in Young Adults Predicts Airflow Obstruction 20 Years Later 
The American journal of medicine  2010;123(5):468.e1-468.e7.
The burden of obstructive lung disease is increasing, yet there are limited data on its natural history in young adults.
To determine in a prospective cohort of generally healthy young adults the influence of early adult lung function on the presence of airflow obstruction in middle age.
Longitudinal study of 2,496 adults who were 18-30 years of age at entry, did not report having asthma, and returned at Year 20. Airflow obstruction was defined as an FEV1/FVC ratio less than the lower limit of normal.
Measurements and Main Results
Airflow obstruction was present in 6.9% and 7.8% of participants at Years 0 and 20. Less than 10% of participants with airflow obstruction self-reported COPD. In cross sectional analyses airflow obstruction was associated with less education, smoking, and self-reported COPD. Low FEV1 and FEV1/FVC and airflow obstruction in young adults were associated with low lung function and airflow obstruction 20 years later. Of those with airflow obstruction at Year 0, 52% had airflow obstruction 20 years later. The FEV1/FVC at Year 0 was highly predictive of airflow obstruction 20 years later (c-statistic 0.91; 95% CI 0.89-0.93). The effect of cigarette smoking on lung function decline with age was most evident in young adults with pre-existing airflow obstruction.
Airflow obstruction is mostly unrecognized in young and middle age adults. A low FEV1, low FEV1/FVC and airflow obstruction in young adults, in addition to smoking, are highly predictive of low lung function and airflow obstruction in middle age.
PMCID: PMC2858051  PMID: 20399325
Airflow obstruction; CARDIA; chronic obstructive pulmonary disease; COPD; natural history
10.  Is there an association between postural balance and pulmonary function in adults with asthma? 
Clinics  2013;68(11):1421-1427.
Asthma may cause systemic repercussions due to its severity and the effects of treatment. Our objective was to compare posture, balance, functional capacity, and quality of life (QOL) according to the severity of disease, as assessed by pulmonary function levels.
This cross-sectional study evaluated fifty individuals with asthma. We compared two groups of adult individuals who were divided according to the median of the forced expiratory volume in one second (FEV1) as follows: group A  =  FEV1>74% predicted; group B  =  FEV1<74% predicted. All patients underwent the following tests: spirometry, whole-body plethysmography, diffusing capacity for carbon monoxide (DLco), respiratory muscle strength, posture assessment, stabilometry, six-minute walking distance (6MWD), and QOL.
All pulmonary function variables exhibited statistically significant differences between the two groups, except for the DLco. The maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and 6MWD were lower in group B. The maximal mediolateral velocity and the mediolateral displacement were significantly different, while the postural changes and QOL were similar between the groups.
In adult individuals with asthma, the pulmonary function is associated with balance control in the mediolateral direction but does not influence the postural changes or QOL.
PMCID: PMC3812553  PMID: 24270954
Asthma; Respiratory Function Tests; Posture; Postural Balance
11.  Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care 
Thorax  2000;55(8):635-642.
BACKGROUND—Chronic obstructive pulmonary disease (COPD) is common although often poorly characterised, particularly in primary care. However, application of guidelines to the management of such patients needs a clear understanding of the phenotype. In particular, the British guidelines for the management of COPD recommend that the diagnosis is based on appropriate symptoms and evidence of airflow obstruction as determined by a forced expiratory volume in one second (FEV1) of <80% of the predicted value and an FEV1/VC ratio of <70%.
METHODS—A study was undertaken of 110 patients aged 40-80 years who had presented to their general practitioner with an acute exacerbation of COPD. The episode was treated at home and, when patients had recovered to the stable state (two months later), they were characterised by full lung function tests and a high resolution computed tomographic (HRCT) scan of the chest.
RESULTS—There was a wide range of impairment of FEV1 which was in the normal range (⩾80%) in 30%, mildly impaired (60-79%) in 18%, moderately impaired (40-59%) in 33%, and severely impaired (<40%) in 19% of patients. A reduced FEV1/VC ratio was present in all patients with an FEV1 of <80% predicted but also in 41% of those with an FEV1 of ⩾80% predicted. Only 5% of patients had a substantial bronchodilator response suggesting a diagnosis of asthma. Emphysema was present in 51% of patients and confined to the upper lobes in most (73% of these patients). HRCT evidence of bronchiectasis was noted in 29% of patients and was predominantly tubular; most (81%) were current or ex-smokers. A solitary pulmonary nodule was seen on 9% of scans and unsuspected lung malignancy was diagnosed in two patients.
CONCLUSIONS—This study confirms that COPD in primary care is a heterogeneous condition. Some patients do not fulfil the proposed diagnostic criteria with FEV1 of ⩾80% predicted but they may nevertheless have airflow obstruction. Bronchiectasis is common in this group of patients, as is unsuspected malignancy. These findings should be considered when developing recommendations for the investigation and management of COPD in the community.

PMCID: PMC1745831  PMID: 10899238
12.  COPD and cognitive impairment: the role of hypoxemia and oxygen therapy 
Several studies have shown an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment. These studies have been limited by methodological issues such as diagnostic uncertainty, cross-sectional design, small sample size, or lack of appropriate referent group. This study aimed to elucidate the association between COPD and the risk of cognitive impairment compared to referent subjects without COPD. In patients with established COPD, we evaluated the impact of disease severity and impairment of respiratory physiology on cognitive impairment and the potential mitigating role of oxygen therapy.
We used the Function, Living, Outcomes and Work (FLOW) cohort study of adults with COPD (n = 1202) and referent subjects matched by age, sex, and race (n = 302) to study the potential risk factors for cognitive impairment among subjects with COPD. Cognitive impairment was defined as a Mini-Mental State Exam score of <24 points. Disease severity was using Forced Expiratory Volume in one second (FEV1); the validated COPD Severity Score; and the BMI (Body Mass Index), Obstruction, Dyspnea, Exercise Capacity (BODE) Index. Multivariable analysis was used to control for confounding by age, sex, race, educational attainment, and cigarette smoking.
COPD was associated with a substantive risk of cognitive impairment compared to referent subjects (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.043–6.64). Among COPD patients, none of the COPD severity measures were associated with the risk of cognitive impairment (P > 0.20 in all cases). Low baseline oxygen saturation was related to increased risk of cognitive impairment (OR for oxygen saturation ≤88% (OR 5.45; 95% CI 1.014–29.2; P = 0.048). Conversely, regular use of supplemental oxygen therapy decreased the risk for cognitive impairment (OR 0.14; 95% CI 0.07–0.27; P < 0.0001).
COPD is a major risk factor for cognitive impairment. Among patients with COPD, hypoxemia is a major contributor and regular use of home oxygen is protective. Health care providers should consider screening their COPD patients for cognitive impairment.
PMCID: PMC2939681  PMID: 20856825
chronic obstructive pulmonary disease
13.  Association of mast cells with lung function in chronic obstructive pulmonary disease 
Respiratory Research  2008;9(1):64.
In asthma, higher chymase positive mast cell (MC-C) numbers are associated with less airway obstruction. In COPD, the distribution of MC-C and tryptase positive mast cells (MC-T) in central and peripheral airways, and their relation with lung function, is unknown. We compared MC-T and MC-C distributions in COPD and controls without airflow limitation, and determined their relation with lung function.
Lung tissue sections from 19 COPD patients (median [interquartile range] FEV1% predicted 56 [23–75]) and 10 controls were stained for tryptase and chymase. Numbers of MC-T and MC-C were determined in different regions of central and peripheral airways and percentage of degranulation was determined.
COPD patients had lower MC-T numbers in the subepithelial area of central airways than controls. In COPD, MC-T numbers in the airway wall and more specifically in the epithelium and subepithelial area of peripheral airways correlated positively with FEV1/VC (Spearman's rho (rs) 0.47, p = 0.05 and rs 0.48, p = 0.05, respectively); MC-C numbers in airway smooth muscle of peripheral airways correlated positively with FEV1% predicted (rs 0.57, p = 0.02). Both in COPD patients and controls the percentage of degranulated MC-T and MC-C mast cells was higher in peripheral than in central airways (all p < 0.05), but this was not different between the groups.
More MC-T and MC-C in peripheral airways correlate with better lung function in COPD patients. It is yet to determine whether this reflects a protective association of mast cells with COPD pathogenesis, or that other explanations are to be considered.
PMCID: PMC2542362  PMID: 18783610
14.  Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease? 
Thorax  2000;55(3):189-193.
BACKGROUND—It has been suggested that oxidative stress is an important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have shown that an oxidant/antioxidant imbalance occurs in the distal air spaces of smokers and in patients with COPD which is reflected systemically in the plasma. A study was undertaken to determine whether plasma antioxidant status correlated with lung function as assessed by forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in smokers and patients with COPD.
METHODS—Plasma antioxidant capacity, assessed by the Trolox equivalent antioxidant capacity (TEAC) as an index of overall systemic oxidative stress, and protein thiol levels were measured in 95patients with stable COPD, in 82 healthy smokers, and in 37 healthy non-smokers.
RESULTS—Mean (SE) plasma TEAC levels were significantly decreased in patients with COPD (0.81 (0.03) mmol/l, p<0.001) and in healthy smokers (0.87 (0.04) mmol/l, p<0.001) compared with healthy non-smokers (1.31 (0.11) mmol/l). The mean differences in plasma antioxidant capacity (mM) were (0.81, 95% confidence interval (CI) 0.22 to 1.48), (0.87, 95% CI 0.2 to 1.46), and (1.31, 95% CI 1.09 to 1.58) in patients with COPD, healthy smokers, and healthy non-smokers, respectively. This reduction was associated with a 29% (95% CI 18 to 38) and a 30% (95% CI 19 to 40) decrease in plasma protein thiol levels in COPD patients and smokers, respectively. Current smoking was not the main contributor to the reduction in antioxidant capacity in patients with COPD as those patients who were still smokers had similar TEAC levels (mean (SE) 0.78 (0.05); n = 25) to those who had stopped smoking (0.84 (0.02); n = 70). No significant correlations were found between spirometric data measured as FEV1 % predicted or FEV1/FVC % predicted and the plasma levels of TEAC in patients with COPD, healthy smokers, or healthy non-smokers. Similarly, there was no significant correlation between FEV1 %predicted or FEV1/FVC % predicted and the levels of plasma protein thiols in the three groups.
CONCLUSIONS—These data confirm decreased antioxidant capacity in smokers and patients with COPD, indicating the presence of systemic oxidative stress. However, no relationship was found between protein thiols or TEAC levels and measurements of airflow limitation in either smokers or in patients with COPD.

PMCID: PMC1745692  PMID: 10679536
15.  Respiratory health of workers exposed to metal dusts and foundry fumes in a copper refinery. 
OBJECTIVES--To assess airflow limitation in workers exposed long term to metal dust, the prevalence of pleural plaques in those workers exposed in the past to asbestos, the influence of pleural plaques on lung function, and the possible association with airway disease caused by asbestos. METHODS--A cross sectional and longitudinal (seven year) survey of 494 long term (mean (SEM) 21(1) years) workers in a copper refinery was carried out from medical questionnaires, chest radiographs, and forced spirometry. RESULTS--The prevalence of lifetime non-smokers was 19%, current smokers 39%, and ex-smokers 42%. The prevalence of chronic obstructive pulmonary diseases (COPD) (forced expiratory volume in one second (FEV1) < 80% predicted) was 5%, small airway dysfunction (SAD) (maximal mid-expiratory flow (MMEF) < 60% predicted) was 7%, and this did not differ from the control population. The COPD and SAD were associated with cumulative smoking index but not with the cumulative work years at the plant or with any type of work at the plant. The mean (SEM) reduction of FEV1 was 20(7) ml in non-smokers, 26(4) ml in smokers, and 26(5) ml in ex-smokers (P > 0.05). In the smokers and ex-smokers with COPD, the loss of FEV1 was 53(10) (P < 0.02). The prevalence of pleural plaques was 11% (P < 0.0001); pleural plaques were found in older workers with known exposure to asbestos. The pleural plaques were circumscribed and associated with a non-significant 196 ml reduction in forced vital capacity (FVC) and non-significant reduction of FVC over time. The pleural plaques were not associated with COPD or SAD. The cumulative smoking index obtained by a technician did not differ from that by a chest physician. CONCLUSIONS--Despite exposures to asbestos that produced pleural plaques and exposures to metal dusts and foundry fumes the long term workers of this plant did not have excessive prevalence of COPD or SAD. The data suggest that low level long term exposure to metal dusts, gases, and foundry fumes do not necessarily cause respiratory dysfunction, circumscribed pleural plaques with low grades of width and extent do not reduce FVC significantly, and exposure to asbestos dust that produced pleural plaques does not necessarily produce airway dysfunction.
PMCID: PMC1128188  PMID: 7735395
16.  Eosinophil and T cell markers predict functional decline in COPD patients 
Respiratory Research  2009;10(1):113.
The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease.
Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines.
Results and Discussion
Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05).
These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.
PMCID: PMC2785783  PMID: 19925666
17.  Alternative methods for assessing bronchodilator reversibility in chronic obstructive pulmonary disease 
Thorax  2001;56(9):713-720.
BACKGROUND—Bronchodilator reversibility testing is recommended in all patients with chronic obstructive pulmonary disease (COPD) but does not predict improvements in breathlessness or exercise performance. Two alternative ways of assessing lung mechanics—measurement of end expiratory lung volume (EELV) using the inspiratory capacity manoeuvre and application of negative expiratory pressure (NEP) during tidal breathing to detect tidal airflow limitation—do relate to the degree of breathlessness in COPD. Their usefulness as end points in bronchodilator reversibility testing has not been examined.
METHODS—We studied 20 patients with clinically stable COPD (mean age 69.9 (1.5) years, 15 men, forced expiratory volume in one second (FEV1) 29.5 (1.6)% predicted) with tidal flow limitation as assessed by their maximum flow-volume loop. Spirometric parameters, slow vital capacity (SVC), inspiratory capacity (IC), and NEP were measured seated, before and after nebulised saline, and at intervals after 5 mg nebulised salbutamol and 500 µg nebulised ipratropium bromide. The patients attended twice and the treatment order was randomised.
RESULTS—Mean FEV1, FVC, SVC, and IC were unchanged after saline but the degree of tidal flow limitation varied. FEV1 improved significantly after salbutamol and ipratropium (0.11 (0.02) l and 0.09 (0.02) l, respectively) as did the other lung volumes with further significant increases after the combination. Tidal volume and mean expiratory flow increased significantly after all bronchodilators but breathlessness fell significantly only after the combination treatment. The initial NEP score was unrelated to subsequent changes in lung volume.
CONCLUSIONS—NEP is not an appropriate measurement of acute bronchodilator responsiveness. Changes in IC were significantly larger than those in FEV1 and may be more easily detected. However, our data showed no evidence for separation of "reversible" and "irreversible" groups whatever outcome measure was adopted.

PMCID: PMC1746134  PMID: 11514693
18.  SERPINE2 haplotype as a risk factor for panlobular type of emphysema 
BMC Medical Genetics  2011;12:157.
SERPINE2 (serpin peptidase inhibitor, clade E, member 2) has previously been identified as a positional candidate gene for chronic obstructive pulmonary disease (COPD) and has subsequently been associated to COPD and emphysema in several populations. We aimed to further examine the role of SERPINE2 polymorphisms in the development of pulmonary emphysema and different emphysema subtypes.
Four single nucleotide polymorphisms (SNPs) in SERPINE2 were analyzed from 951 clinically and radiologically examined Finnish construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high-resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusing capacity (DLCO), and specific diffusing capacity (DLCO/VA).
Three of the studied SERPINE2 SNPs (rs729631, rs975278, and rs6748795) were found to be in tight linkage disequilibrium. Therefore, only one of these SNPs (rs729631) was included in the subsequent analyses, in addition to the rs840088 SNP which was in moderate linkage with the other three studied SNPs. The rs729631 SNP showed a significant association with panlobular emphysema (p = 0.003). In further analysis, the variant allele of the rs729631 SNP was found to pose over two-fold risk (OR 2.22, 95% CI 1.05-4.72) for overall panlobular changes and over four-fold risk (OR 4.37, 95% CI 1.61-11.86) for pathological panlobular changes. A haplotype consisting of variant alleles of both rs729631 and rs840088 SNPs was found to pose an almost four-fold risk for overall panlobular (OR 3.72, 95% CI 1.56-8.90) and subnormal (OR 3.98, 95% CI 1.55-10.20) emphysema.
Our results support the previously found association between SERPINE2 polymorphisms and pulmonary emphysema. As a novel finding, our study suggests that the SERPINE2 gene may in particular be involved in the development of panlobular changes, i.e., the same type of changes that are involved in alpha-1-antitrypsin (AAT) -deficiency.
PMCID: PMC3269992  PMID: 22145704
19.  Determinants of airflow obstruction in severe alpha‐1‐antitrypsin deficiency 
Thorax  2007;62(9):806-813.
Severe α1‐antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.
The AAT Genetic Modifier Study is a multicentre family‐based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted).
In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non‐index cases (p<0.01). Men had lower pre‐ and post‐bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non‐index groups were examined separately, with men representing the majority of non‐index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non‐index men but not women.
In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
PMCID: PMC2117297  PMID: 17389752
20.  AB 20. Mean platelet volume and platelet distribution width in patients with chronic obstructive pulmonary disease 
Journal of Thoracic Disease  2012;4(Suppl 1):AB20.
In patients with COPD, there is an evidence of platelet activation due to chronic hypoxia and systemic inflammation. Aim of the study was to evaluate Mean Platelet Volume (MPV) and Platelet Distribution Width (PDW), markers of platelet activation, in patients with Chronic Obstructive Pulmonary Disease (COPD), and to investigate possible associations with pulmonary function testing [Forced expiratory volume in 1 second (FEV1) and Forced vital capacity (FVC)].
Patients and methods
Current smokers with stable COPD (n=85) and smokers without airflow limitation (n=35) were included. To all of them pulmonary function testing was performed and count of white blood cells (WBC) platelets, as well as MPV and PDW were measured.
In smokers with COPD, MPV was significantly higher (mean value 10.563±1.531 vs. 9.956±1.046 fl, P<0.05) than in control group. WBC was also significantly higher in patients with COPD than in controls (9045.53±2664.34/μL vs. 7018.79±1989.74/μL, P<0.001). A significant correlation between MPV and WBC in COPD patients was revealed, especially in those at GOLD Stage III (r=0.475, P=0.012) and IV (r=0.367, P=0.033). WBC count was correlated with FEV1/FVC values (P=0.044). MPV did not correlate with any indices of COPD severity.
In patients with COPD, MPV and WBC levels are significantly correlated and are elevated in comparison to smokers with normal pulmonary function. WBC count was negatively correlated with FEV1/FVC values.
PMCID: PMC3537346
21.  COPD and disease-specific health status in a working population 
Respiratory Research  2013;14(1):61.
It has been debated whether treatment should be started early in subjects with mild to moderate COPD. An impaired health status score was associated with a higher probability of being diagnosed with COPD as compared with undiagnosed COPD.
To investigate the health status in a healthy working population, to determine reference scores for healthy non-smoking subjects, and to investigate the relationship between their health status and airflow limitation.
A total of 1333 healthy industrial workers aged ≥40 years performed spirometry and completed the St. George’s Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT).
The prevalence of COPD defined by the fixed ratio of the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) was 10.9%, and the prevalence defined by the Lower Limit of Normal was 5.0%. All SGRQ and CAT scores were skewed to the milder end. In 512 non-smoking subjects with normal spirometry, the mean SGRQ score was 5.7, and the mean CAT score was 5.8. In 145 people with COPD defined by the fixed ratio, the mean SGRQ score was 7.9, with a zero score in 6.9% of the subjects. Using the CAT, the mean score was 7.3, with 7.6% of the scores being zero. The scores in patients identified using the Lower Limit of Normal approach were: SGRQ 8.4 (13.4% had a score of zero) and CAT 7.4 (13.4% had a score of zero). Although the 95th percentiles of the Total, Symptoms, Activity, and Impact scores of the SGRQ and CAT sores were 13.8, 34.0, 23.4, 7.2 and 13.6 in the 512 healthy non-smoking subjects, respectively, they were also distributed under their upper limits in over 80% of the COPD subjects.
The COPD-specific health status scores in a working population were good, even in those with spirometrically diagnosed COPD. All scores were widely distributed in both healthy non-smoking subjects and in subjects with COPD, and the score distribution overlapped remarkably between these two groups. This suggests that symptom-based methods are not suitable screening tools in a healthy general population.
PMCID: PMC3679860  PMID: 23725096
Chronic obstructive pulmonary disease; St. George’s Respiratory Questionnaire; Symptoms and COPD; Smoking and health; Health related quality of life
22.  Relationship between peripheral airway function and patient-reported outcomes in COPD: a cross-sectional study 
Health status, dyspnea and psychological status are important clinical outcomes in chronic obstructive pulmonary disease (COPD). However, forced expiratory volume in one second (FEV1) measured by spirometry, the standard measurement of airflow limitation, has only a weak relationship with these outcomes in COPD. Recently, in addition to spirometry, impulse oscillometry (IOS) measuring lung resistance (R) and reactance (X) is increasingly being used to assess pulmonary functional impairment.
We aimed to identify relationships between IOS measurements and patient-reported outcomes in 65 outpatients with stable COPD. We performed pulmonary function testing, IOS, high-resolution computed tomography (CT), and assessment of health status using the St. George's Respiratory Questionnaire (SGRQ), dyspnea using the Medical Research Council (MRC) scale and psychological status using the Hospital Anxiety and Depression Scale (HADS). We then investigated the relationships between these parameters. For the IOS measurements, we used lung resistance at 5 and 20 Hz (R5 and R20, respectively) and reactance at 5 Hz (X5). Because R5 and R20 are regarded as reflecting total and proximal airway resistance, respectively, the fall in resistance from R5 to R20 (R5-R20) was used as a surrogate for the resistance of peripheral airways. X5 was also considered to represent peripheral airway abnormalities.
R5-R20 and X5 were significantly correlated with the SGRQ and the MRC. These correlation coefficients were greater than when using other objective measurements of pulmonary function, R20 on the IOS and CT instead of R5-R20 and X5. Multiple regression analyses showed that R5-R20 or X5 most significantly accounted for the SGRQ and MRC scores.
IOS measurements, especially indices of peripheral airway function, are significantly correlated with health status and dyspnea in patients with COPD. Therefore, in addition to its simplicity and non-invasiveness, IOS may be a useful clinical tool not only for detecting pulmonary functional impairment, but also to some extent at least estimating the patient's quality of daily life and well-being.
PMCID: PMC2841100  PMID: 20205936
23.  Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease 
Thorax  2012;68(7):670-676.
Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is characterised by airflow obstruction that is not fully reversible and is a major global cause of morbidity and mortality. The most widely used marker of disease severity and progression is FEV1. However, FEV1 correlates poorly with both symptoms and other measures of disease progression and thus there is an urgent need for other biological markers to better characterise individuals with COPD. Fibrinogen is an acute phase plasma protein that has emerged as a promising biomarker in COPD. Here we review the current clinical evidence linking fibrinogen with COPD and its associated co-morbidities and discuss its potential utility as a biomarker.
Searches for appropriate studies were undertaken on PubMed using search terms fibrinogen, COPD, emphysema, chronic bronchitis, FEV1, cardiovascular disease, exacerbation and mortality.
There is strong evidence of an association between fibrinogen and the presence of COPD, the presence and frequency of exacerbations and with mortality. Fibrinogen is associated with disease severity but does not predict lung function decline, a measure used as a surrogate for disease activity. The role of fibrinogen in identifying inflammatory co morbidities, particularly cardiovascular disease, remains unclear. Fibrinogen is reduced by p38 mitogen-activated protein kinase inhibitors in individuals with stable disease and by oral corticosteroids during exacerbations.
Fibrinogen is likely to be a useful biomarker to stratify individuals with COPD into those with a high or low risk of future exacerbations and may identify those with a higher risk of mortality.
PMCID: PMC3711372  PMID: 22744884
Fibrinogen; inflammation; COPD; biomarker
24.  Budesonide/formoterol combination in COPD: a US perspective 
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 μg; Symbicort™, AstraZeneca, Sweden) delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden) but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD.
PMCID: PMC2962302  PMID: 21037960
inhaled steroid; bronchodilator; β2-agonist; lung function; quality of life; COPD exacerbations
25.  Association of plasma sRAGE, but not esRAGE with lung function impairment in COPD 
Respiratory Research  2014;15(1):24.
Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and DLCO, and with different circulating AGEs.
Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV1 (%predicted) and FEV1/VC (%) were measured in both groups; DLCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE Nϵ-(carboxymethyl) lysine (CML) was decreased, Nϵ-(carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls.
Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p = 0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV1 (r = 0.235, p = 0.032), FEV1/VC (r = 0.218, p = 0.047), and DLCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003).
Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV1, FEV1/VC and DLCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity.
PMCID: PMC3944004  PMID: 24564838

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