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1.  Genome-wide Association Study Identifies BICD1 as a Susceptibility Gene for Emphysema 
Rationale: Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors.
Objectives: To identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with COPD.
Methods: We performed a genome-wide association study (GWAS) of emphysema determined from chest computed tomography scans with a total of 2,380 individuals with COPD in three independent cohorts of white individuals from (1) a cohort from Bergen, Norway, (2) the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and (3) the National Emphysema Treatment Trial (NETT). We tested single-nucleotide polymorphism associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait (percentage of lung voxels less than –950 Hounsfield units) in all three cohorts.
Measurements and Main Results: We identified association of a single-nucleotide polymorphism in BICD1 with the presence or absence of emphysema (P = 5.2 × 10−7 with at least mild emphysema vs. control subjects; P = 4.8 × 10−8 with moderate and more severe emphysema vs. control subjects).
Conclusions: Our study suggests that genetic variants in BICD1 are associated with qualitative emphysema in COPD. Variants in BICD1 are associated with length of telomeres, which suggests that a mechanism linked to accelerated aging may be involved in the pathogenesis of emphysema.
Clinical trial registered with www.clinicaltrials.gov (NCT00292552).
doi:10.1164/rccm.201004-0541OC
PMCID: PMC3040393  PMID: 20709820
emphysema; chronic obstructive pulmonary disease; BICD1; single-nucleotide polymorphism
2.  TNF-α is associated with loss of lean body mass only in already cachectic COPD patients 
Respiratory Research  2012;13(1):48.
Background
Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years.
Methods
The patients, aged 40–76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models.
Results
At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry.
Conclusion
This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.
doi:10.1186/1465-9921-13-48
PMCID: PMC3487870  PMID: 22708547
Inflammation; TNF-α; COPD; Cachexia
3.  Predictors' Factors of Nutritional Status of Male Chronic Obstructive Pulmonary Disease Patients 
ISRN Nursing  2012;2012:782626.
Chronic obstructive pulmonary disease (COPD) is a systemic disease that leads to weight loss and muscle dysfunction resulting in an increase in mortality. This study aimed to determine the prevalence rate of malnutrition and nutritional status and also factors associated with nutritional status. A total of 149 subjects were involved in the cross-sectional study. The study was conducted at two medical centers in Kuala Lumpur, Malaysia. The results of the study showed that malnutrition was more prevalent (52.4%) in the subjects with severe stages of COPD as compared to mild and moderate COPD stages (26.2%) (P < 0.05). Fat-free mass depletion as assessed using fat-free mass index (FFMI) affected 41.9% of the subjects. Plasma vitamin A, peak expiratory flow (PEF), and handgrip were the predictors for body mass index (BMI) (R2 = 0.190, P < 0.001). Plasma vitamin A and force expiratory volume in one second (FEV1) were the predictors of FFMI (R2 = 0.082, P = 0.007). BMI was the predictor of respiratory factors, that is, FEV1% predicted (R2 = 0.052, P = 0.011). It can be concluded that there is a need to identify malnourished COPD patients for an appropriate nutrition intervention.
doi:10.5402/2012/782626
PMCID: PMC3504379  PMID: 23209935
4.  Body Composition in Severe Refractory Asthma: Comparison with COPD Patients and Healthy Smokers 
PLoS ONE  2010;5(10):e13233.
Background
Body composition is an important parameter for patients with chronic obstructive pulmonary disease (COPD) whereas the association between asthma and obesity is not fully understood. The impact of severe refractory asthma (SRA) on fat free mass (FFM) has not been investigated.
Methodology and Principal Findings
213 subjects (70 healthy smokers, 71 COPD patients and 72 asthma patients) without significant comorbidities were included in the study. In all patients, body composition assessment (using bioelectrical impendance analysis, skinfold and anthropometric measurements) and spirometry were performed. Differences in fat free mass index (FFMI) between groups were assessed and determinants of FFMI in asthma were evaluated. Patients with SRA had lower values of FFMI compared to patients with mild-to-moderate asthma [18.0(17.3–18.3)–19.5(18.4–21.5), p<0.001], despite the fact that they were more obese. The levels of FFMI in SRA were lower than those of GOLD stage I–III COPD and comparable to those of stage IV COPD patients [18.0(17.3–18.3)–18.8(17.8–20.1), p = ns]. These differences were present even after proper adjustments for sex, age, smoking status, daily dose of inhaled corticosteroids (ICS) and daily use of oral corticosteroids (OCS). In multivariate analysis, independent predictors of FFMI in asthmatic patients were age, use of OCS and the presence of SRA, but not smoking, sex or cumulative dose of ICS used.
Conclusions and Significance
SRA is related to the presence of low FFMI that is comparable to that of GOLD stage IV COPD. The impact of this observation on asthma mechanisms and outcomes should be further investigated in large prospective studies.
doi:10.1371/journal.pone.0013233
PMCID: PMC2950851  PMID: 20949085
5.  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
6.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci 
PLoS Genetics  2009;5(3):e1000421.
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
Author Summary
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.
doi:10.1371/journal.pgen.1000421
PMCID: PMC2650282  PMID: 19300482
7.  Comprehensive out-patient pulmonary rehabilitation: Treatment outcomes in early and late stages of chronic obstructive pulmonary disease 
Annals of Thoracic Medicine  2011;6(2):70-76.
BACKGROUND:
The aim was to evaluate the outcomes of a comprehensive pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) and to establish whether in early disease stage PR is as effective as in late stages of disease.
METHODS:
A total of 55 stable COPD patients, 28 with early and 27 with late disease stages, were assessed. Patients underwent a comprehensive out-patient PR program for 8 weeks. To eluciate the effects of PR and compare the level of improvement; lung function, dyspnea sensation [Medical Research Council (MRC)], body composition [body mass index (BMI), fat free mass (FFM), fat free mass index (FFMI)], exercise capacity [incremental shuttle walking test, endurance shuttle walking test], health related quality of life (HRQoL) with St. George Respiratory Disease Questionnaire, psycohological status (Hospital anxiety–depression (HAD) scale) were evaluated before and after PR.
RESULTS:
At the end of PR in the early disease stage group, the improvement in forced vital capacity (FVC) reached a statistically significant level (P < 0.05). In both disease stages, there were no significant differences in BMI, FFM, and FFMI. The decrease in exertional dyspnea for the two groups evaluated with the modified BORG scale were not found statistically significant, though the dyspnea scores evaluated with MRC showed significant improvements (P < 0.001). HRQoL and exercise capacity were significantly improved for the two groups (P < 0.001). Psychological status evaluated with the HAD scale improved after PR (P < 0.001) both in early and late stages. Gainings in the study parameters did not differ in the early and the late disease stages.
CONCLUSIONS:
These results showed that patients with COPD had benefited from a comprehensive PR program in an out-patient setting regardless of disease severity. Even patients with earlier stage of disease should be referred and encouraged to participate in a PR program.
doi:10.4103/1817-1737.78420
PMCID: PMC3081559  PMID: 21572695
Chronic obstructive pulmonary disease; disease severity; functional status; pulmonary rehabilitation; shuttle walk test
8.  Body mass index and prognosis in patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease 
Background
Nutritional status, weight loss and cachexia have important prognostic implications in patients with chronic obstructive pulmonary disease (COPD). Body mass index (BMI) has been implicated in COPD risk assessment, but information is mostly limited to composite scores or to patients with stable disease. We aimed to analyse the association between BMI and mortality in acute exacerbation of COPD.
Methods
This retrospective survey included 968 patients hospitalized due to acute exacerbation of COPD at the University Clinic Golnik from February 2002 to June 2007. Vital status was ascertained with Central Population Registry, and database was censored on November 1, 2008.
Results
Median BMI was 25.08 kg/m2 (interquartile range, 21.55–29.05 kg/m2) and 210 patients (22%) had BMI < 21 kg/m2. During median follow-up of 3.26 years (1.79–4.76 years), 430 patients (44%) died. Lowest mortality was found for BMI 25.09–29.05 kg/m2. When divided per BMI decile, mortality was lowest for BMI 25.09–26.56 kg/m2 (33%). In univariate analysis, BMI per quartile and BMI per unit increase were predictive for all-cause mortality. In an adjusted model, BMI per 1 kg/m2 unit increase was associated with 5% less chance of death (hazard ratio 0.95, 95% confidence interval 0.93–0.97).
Conclusions
Low BMI < 21 kg/m2 is frequent in patients hospitalized due to acute exacerbation of COPD. Higher BMI was independently predictive of better long-term survival. A better outcome in obese patients compared to normal weight is in contrast to primary prevention data but concurs with observations of an obesity paradox in other cardiovascular diseases.
doi:10.1007/s13539-011-0023-9
PMCID: PMC3118008  PMID: 21766053
Chronic obstructive pulmonary disease; Body mass index; Cachexia; Survival
9.  Body mass index and prognosis in patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease 
Background
Nutritional status, weight loss and cachexia have important prognostic implications in patients with chronic obstructive pulmonary disease (COPD). Body mass index (BMI) has been implicated in COPD risk assessment, but information is mostly limited to composite scores or to patients with stable disease. We aimed to analyse the association between BMI and mortality in acute exacerbation of COPD.
Methods
This retrospective survey included 968 patients hospitalized due to acute exacerbation of COPD at the University Clinic Golnik from February 2002 to June 2007. Vital status was ascertained with Central Population Registry, and database was censored on November 1, 2008.
Results
Median BMI was 25.08 kg/m2 (interquartile range, 21.55–29.05 kg/m2) and 210 patients (22%) had BMI < 21 kg/m2. During median follow-up of 3.26 years (1.79–4.76 years), 430 patients (44%) died. Lowest mortality was found for BMI 25.09–29.05 kg/m2. When divided per BMI decile, mortality was lowest for BMI 25.09–26.56 kg/m2 (33%). In univariate analysis, BMI per quartile and BMI per unit increase were predictive for all-cause mortality. In an adjusted model, BMI per 1 kg/m2 unit increase was associated with 5% less chance of death (hazard ratio 0.95, 95% confidence interval 0.93–0.97).
Conclusions
Low BMI < 21 kg/m2 is frequent in patients hospitalized due to acute exacerbation of COPD. Higher BMI was independently predictive of better long-term survival. A better outcome in obese patients compared to normal weight is in contrast to primary prevention data but concurs with observations of an obesity paradox in other cardiovascular diseases.
doi:10.1007/s13539-011-0023-9
PMCID: PMC3118008  PMID: 21766053
Chronic obstructive pulmonary disease; Body mass index; Cachexia; Survival
10.  Polymorphisms in Surfactant Protein–D Are Associated with Chronic Obstructive Pulmonary Disease 
Chronic obstructive pulmonary disease (COPD) is characterized by alveolar destruction and abnormal inflammatory responses to noxious stimuli. Surfactant protein–D (SFTPD) is immunomodulatory and essential to host defense. We hypothesized that polymorphisms in SFTPD could influence the susceptibility to COPD. We genotyped six single-nucleotide polymorphisms (SNPs) in surfactant protein D in 389 patients with COPD in the National Emphysema Treatment Trial (NETT) and 472 smoking control subjects from the Normative Aging Study (NAS). Case-control association analysis was performed using Cochran–Armitage trend tests and multivariate logistic regression. The replication of significant associations was attempted in the Boston Early-Onset COPD Study, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and the Bergen Cohort. We also correlated SFTPD genotypes with serum concentrations of surfactant protein–D (SP-D) in the ECLIPSE Study. In the NETT–NAS case-control analysis, four SFTPD SNPs were associated with susceptibility to COPD: rs2245121 (P = 0.01), rs911887 (P = 0.006), rs6413520 (P = 0.004), and rs721917 (P = 0.006). In the family-based analysis of the Boston Early-Onset COPD Study, rs911887 was associated with prebronchodilator and postbronchodilator FEV1 (P = 0.003 and P = 0.02, respectively). An intronic SNP in SFTPD, rs7078012, was associated with COPD in the ECLIPSE Study and the Bergen Cohort. Multiple SFTPD SNPs were associated with serum SP-D concentrations in the ECLIPSE Study. We demonstrated an association of polymorphisms in SFTPD with COPD in multiple populations. We demonstrated a correlation between SFTPD SNPs and SP-D protein concentrations. The SNPs associated with COPD and SP-D concentrations differed, suggesting distinct genetic influences on susceptibility to COPD and SP-D concentrations.
doi:10.1165/rcmb.2009-0360OC
PMCID: PMC3095932  PMID: 20448057
COPD; surfactant protein–D; single-nucleotide polymorphisms; genetics
11.  Nutritional Aspects of Chronic Obstructive Pulmonary Disease 
It is clear that being underweight is a poor prognostic sign in chronic obstructive pulmonary disease (COPD). It is also clear that undernutrition is at least in part associated with the severity of airflow obstruction. While both weight and body mass index are useful screening tools in the initial nutritional evaluation, fat-free mass (FFM) may be a better marker of undernutrition in patients with COPD. The causes of cachexia in patients with COPD are multifactorial and include decreased oral intake, the effect of increased work of breathing due to abnormal respiratory mechanics, and the effect of chronic systemic inflammation. Active nutritional supplementation in undernourished patients with COPD can lead to weight gain and improvements in respiratory muscle function and exercise performance. However, long-term effects of nutritional supplementation are not clear. In addition, the optimal type of nutritional supplementation needs to be explored further. The role of novel forms of treatment, such as androgens or appetite stimulants designed to increase FFM, also needs to be further studied. Thus, in the absence of definitive data, it cannot be said that long-term weight gain, either using enhanced caloric intake, with or without anabolic steroids or appetite stimulants, offers survival or other benefits to patients with COPD. However, there are indications from single-center trials that this is an avenue well worth exploring.
doi:10.1513/pats.200707-092ET
PMCID: PMC2645329  PMID: 18453365
chronic obstructive pulmonary disease; nutrition; cachexia; testosterone; megace
12.  Association between markers of emphysema and more severe chronic obstructive pulmonary disease 
Thorax  2006;61(12):1037-1042.
Background
The predominant emphysema phenotype is associated with more severe airflow limitation in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate whether COPD patients, with or without emphysema quantitatively confirmed by high resolution computed tomography (HRCT), have different COPD severity as assessed by the BODE index (body mass index, airflow obstruction, dyspnoea, exercise performance) and inspiratory capacity to total lung capacity ratio (IC/TLC), and by different biological markers of lung parenchymal destruction.
Methods
Twenty six outpatients with COPD and eight healthy non‐smokers were examined. Each subject underwent HRCT scanning, pulmonary function tests, cell counts, and measurements of neutrophil elastase, matrix metalloproteinase (MMP)‐9 and tissue inhibitor of metalloproteinase (TIMP)‐1 in induced sputum, as well as measurement of desmosine, a marker of elastin degradation in urine, plasma and sputum.
Results
Patients with HRCT confirmed emphysema had a higher BODE index and lower IC/TLC ratio than subjects without HRCT confirmed emphysema and controls. Forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity ratio, and carbon monoxide transfer coefficient were lower, whereas the number of eosinophils, MMP‐9, and the MMP‐9/TIMP‐1 ratio in sputum were higher in patients with emphysema. In COPD patients the number of sputum eosinophils was the biological variable that correlated positively with the HRCT score of emphysema (p = 0.04).
Conclusions
These results suggest that COPD associated with HRCT confirmed emphysema is characterised by more severe lung function impairment, more intense airway inflammation and, possibly, more serious systemic dysfunction than COPD not associated with HRCT confirmed emphysema.
doi:10.1136/thx.2006.058321
PMCID: PMC2117071  PMID: 16769715
chronic obstructive pulmonary disease; emphysema; biological markers; outcomes
13.  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
14.  Predictive properties of different multidimensional staging systems in patients with chronic obstructive pulmonary disease 
Background
Chronic obstructive pulmonary disease (COPD) is considered to be a respiratory disease with systemic manifestations. Some multidimensional staging systems, not based solely on the level of airflow limitation, have been developed; however, these systems have rarely been compared.
Methods
We previously recruited 150 male outpatients with COPD for an analysis of factors related to mortality. For this report, we examined the discriminative and prognostic predictive properties of three COPD multidimensional measurements. These indices were the modified BODE (mBODE), which includes body mass index, airflow obstruction, dyspnea, and exercise capacity; the ADO, composed of age, dyspnea, and airflow obstruction; and the modified DOSE (mDOSE), comprising dyspnea, airflow obstruction, smoking status, and exacerbation frequency.
Results
Among these indices, the frequency distribution of the mBODE index was the most widely and normally distributed. Univariate Cox proportional hazards analyses revealed that the scores on three indices were significantly predictive of 5-year mortality of COPD (P < 0.001). The scores on the mBODE and ADO indices were more significantly predictive of mortality than forced expiratory volume in 1 second, the Medical Research Council dyspnea score, and the St. George’s Respiratory Questionnaire total score. However, peak oxygen uptake on progressive cycle ergometry was more significantly related to mortality than the scores on the three indices (P < 0.0001).
Conclusion
The multidimensional staging systems using the mBODE, ADO, and mDOSE indices were significant predictors of mortality in COPD patients, although exercise capacity had a more significant relationship with mortality than those indices. The mBODE index was superior to the others for its discriminative property. Further discussion of the definition of disease severity is necessary to promote concrete multidimensional staging systems as a new disease severity index in guidelines for the management of COPD.
doi:10.2147/COPD.S24420
PMCID: PMC3206768  PMID: 22069363
COPD; multidimensional staging systems; BODE index; ADO index; DOSE index
15.  NF-κB activation and iNOS upregulation in skeletal muscle of patients with COPD and low body weight 
Thorax  2004;59(6):483-487.
Background: Weight loss, mostly due to skeletal muscle atrophy, is a frequent and clinically relevant problem in patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying this phenomenon are unclear. This study sought to investigate whether activation of the nuclear transcription factor NF-κB and upregulation of the inducible form of nitric oxide synthase (iNOS) occur in the skeletal muscle of patients with COPD and low body weight as potential molecular mechanisms leading to cachexia
Methods: NF-κB DNA binding activity was determined by electromobility shift assay and the immunoreactivity of its inhibitory subunit IκB-κ and that of iNOS by Western blot analysis in biopsy specimens of the quadriceps femoris muscle of seven COPD patients with normal body mass index (BMI, 27.5 (1) kg/m2) and seven patients with low BMI (18.5 (1) kg/m2).
Results: Compared with patients with normal body weight, those with low BMI showed a 30% increase in NF-κB DNA binding activity, a lower expression of IκB-α (3.37 (0.47) IOD v 5.96 (0.75) IOD, p<0.05; mean difference 2.59; 95% CI –4.53 to –0.65) and higher iNOS expression (1.51 (0.29) IOD v 0.78 (0.11) IOD, p<0.05; mean difference 0.74; 95% CI 0.04 to 1.42).
Conclusions: NF-κB activation and iNOS induction occur in skeletal muscle of COPD patients with low body weight. These changes might contribute to the molecular pathogenesis of cachexia in COPD.
doi:10.1136/thx.2003.017640
PMCID: PMC1747038  PMID: 15170030
16.  Resting energy expenditure and carbohydrate oxidation are higher in elderly patients with COPD: a case control study 
Nutrition Journal  2012;11:37.
Background
Elderly patients with chronic obstructive pulmonary disease (COPD) usually have a compromised nutritional status which is an independent predictor of morbidity and mortality. To know the Resting Energy Expenditure (REE) and the substrate oxidation measurement is essential to prevent these complications. This study aimed to compare the REE, respiratory quotient (RQ) and body composition between patients with and without COPD.
Methods
This case–control study assessed 20 patients with chronic obstructive pulmonary disease attending a pulmonary rehabilitation program. The group of subjects without COPD (control group) consisted of 20 elderly patients attending a university gym, patients of a private service and a public healthy care. Consumption of oxygen (O2) and carbon dioxide (CO2) was determined by indirect calorimetry and used for calculating the resting energy expenditure and respiratory quotient. Body mass index (BMI) and waist circumference (WC) were also measured. Percentage of body fat (%BF), lean mass (kg) and muscle mass (kg) were determined by bioimpedance. The fat free mass index (FFMI) and muscle mass index (MMI) were then calculated.
Results
The COPD group had lower BMI than control (p = 0.02). However, WC, % BF, FFMI and MM-I did not differ between the groups. The COPD group had greater RQ (p = 0.01), REE (p = 0.009) and carbohydrate oxidation (p = 0.002).
Conclusions
Elderly patients with COPD had higher REE, RQ and carbohydrate oxidation than controls.
doi:10.1186/1475-2891-11-37
PMCID: PMC3502439  PMID: 22672689
Chronic obstructive pulmonary disease; Resting energy expenditure; Elderly; Carbohydrate oxidation
17.  Obesity, but not undiagnosed airflow obstruction, is linked to respiratory symptoms and decreased functional capacity in adults without established COPD 
Aims
To delineate the relationship of obesity to airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD).
Methods
We analyzed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilization attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, Six Minute Walk Test (SMWT) and the Short Performance Physical Battery (SPPB). We used multiple regression analyses to test the associations of obesity (BMI≥30kg/m2) and smoking with AO (FEV1/FVC ratio<0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO.
Results
Of 371 subjects (aged 40–65), 69 (19%) manifested AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI: 1.04 – 1.49), while obesity was negatively associated with AO (OR 0.54; 95% CI: 0.30 – 0.98). Obesity was associated with increased odds of reporting dyspnea on exertion (OR 3.6; 95% CI: 2.0 – 6.4), productive cough (OR 2.5; 95% CI: 1.1 – 6.0), and with decrements in SMWT distance (−67 ± 9meters; 95% CI: −84 to −50m) and SPPB score (OR 1.9; 95% CI: 1.1 – 3.5). None of these outcomes were associated with AO.
Conclusions
Although AO and obesity are both common among adults without an established COPD diagnosis, obesity, but not AO, is linked to a higher risk of reporting dyspnea on exertion, productive cough, and poorer functional capacity.
doi:10.4104/pcrj.2012.00028
PMCID: PMC3523806  PMID: 22453663
airflow obstruction; obesity; functional status; health status; dyspnea
18.  Association Between Emphysema Score, Six-Minute Walk and Cardiopulmonary Exercise Tests in COPD 
Background:
High-resolution computed tomography (HRCT) has allowed in detection of airway wall abnormalities and emphysema, whose extent may correlate with the clinical severity of the disease in patients with chronic obstructive pulmonary disease (COPD). Six minute walk test (6MWT) and cardiopulmonary exercise test (CPET) can determine functional status.
Methods:
A study was undertaken to investigate whether the extent of emphysema in COPD patients quantitatively confirmed by HRCT scoring was associated with distance walked, inspiratory capacity (IC) changes after exercise, anaerobic threshold of cardiopulmonary exercise and the BODE index (body mass index, airflow obstruction, dyspnea, exercise performance).
Results:
Seventeen patients with COPD underwent HRCT scanning, 6MWT and CPET. The emphysema score was highly correlated to forced vital capacity (FVC) (r=-0.748, p<0.001), forced expiratory volume in 1 second (FEV1) (r=-0.615, p<0.01), IC post exercise (r=-0.663, p<0.01) and dyspnea score post exercise (r=0.609, p<0.01), but was not associated with the BODE index. The distance walked during 6MWT was inversely correlated to emphysema score (r=-0.557, p<0.05). IC before exercise was highly related to the 6MWT. The change in IC after exercise was associated with the percent decline of oxygen saturation after exercise (r=0.633, p<0.01). Severity of lung emphysema in COPD patients was inversely correlated to VO2 max (r=-0.514, p<0.05) and anaerobic threshold (r=-0.595, p<0.01) of cardiopulmonary exercise.
Conclusions:
These results suggest that COPD associated with emphysema on HRCT is characterized by more severe lung function impairment, greater exercise impairment and cardiopulmonary dysfunction.
doi:10.2174/1874306401206010104
PMCID: PMC3480708  PMID: 23115601
Chronic obstructive pulmonary disease; High-resolution computed tomography; Six-minute walk test; cardiopulmonary exercise test; Inspiratory capacity.
19.  Correlation of BMI and oxygen saturation in stable COPD in Northern India 
Background:
Chronic obstructive pulmonary disease (COPD) is associated with clinically relevant extra pulmonary manifestations; one of them is weight loss. However, there are very few studies from North India available in relation to body mass index (BMI) and Oxygen saturation (SpO2) with COPD.
Aims:
To study the prevalence of undernutrition among stable COPD patients and correlation of COPD severity with SpO2 and BMI.
Settings and Design:
A prospective study was carried out at a tertiary care hospital.
Subjects and Methods:
COPD patients were diagnosed and staged as per global initiative for chronic obstructive lung disease (GOLD) guidelines. SpO2 was measured using pulse oxymeter and BMI categorization was done as per new classification for Asian Indians (2009). Statistical analysis was done using Statistical Package for Social Sciences Version 15.0.
Results:
Out of 147 COPD patients, 85 (57.8%) were undernourished. The prevalence of undernourished BMI was 25%, 50.8%, 61.7%, and 80% in stage I, II, III and IV respectively; statistically significant (P < 0.050). The mean SpO2 was 95.50 ± 1.41, 95.05 ± 2.42, 94.37 ± 2.28 and 93.05 ± 1.39 in stage I, II, III and IV respectively; statistically significant (F = 4.723; P = 0.004).
Conclusions:
The overall prevalence of under nutrition among COPD patients was 57.8%. With increasing COPD stage the BMI and median SpO2 value decreased in progressive manner. Association of SpO2 and COPD stages could be explored further in order to suggest an additional marker of disease severity that would add a new dimension in the management of COPD.
doi:10.4103/0970-2113.125891
PMCID: PMC3960805  PMID: 24669078
BMI; COPD; prevalence; SpO2; undernutrition
20.  Loci Identified by Genome-wide Association Studies Influence Different Disease-related Phenotypes in Chronic Obstructive Pulmonary Disease 
Rationale: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.
Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.
Methods: The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).
Measurements and Main Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10−4), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10−4 and 4.8 × 10−5), and airflow obstruction (P = 0.004 and 1.8 × 10−5) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV1. The HHIP locus was not associated with smoking intensity but was associated with FEV1/FVC (P = 1.9 × 10−4 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.
Conclusions: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.
doi:10.1164/rccm.201002-0151OC
PMCID: PMC3029936  PMID: 20656943
COPD exacerbations; nicotine addiction; high-resolution CT; genetic association analysis; emphysema
21.  Effects of TNF-α and Leptin on Weight Loss in Patients with Stable Chronic Obstructive Pulmonary Disease 
Background
Weight loss is common in patients with chronic obstructive pulmonary disease (COPD). However, the mechanisms of this weight loss are still unclear.
Methods
Sixty male patients with stable COPD and 45 healthy male controls participated in this study. The COPD patients were divided into two groups, that is, the emphysema and chronic bronchitis groups, by the transfer coefficient of carbon monoxide. The body composition, resting energy expenditure (REE), plasma leptin levels and serum tumor necrosis factor-alpha (TNF-α) were measured in all the study participants. The difference and correlation of these parameters were investigated between the two groups.
Results
Emphysematous patients were characterized by a lower body mass index (BMI) and fat-mass (FM) compared with the chronic bronchitis patients (p<0.001). The plasma leptin levels, as corrected for the FM, were not different between the COPD patients and healthy controls (78.3±30.9 pg/mL/kg vs. 70.9±17.3 pg/mL/kg, respectively), and the plasma leptin levels, as adjusted for the FM, were also not different between the two groups of COPD patients. In the chronic bronchitis patients, the plasma leptin concentration was correlated with the BMI (r=0.866, p<0.001) but it was not correlated with the BMI in the emphysema patients. The serum TNF-α levels were higher in the stable COPD patients than those in the controls, but there was no statistical difference (10.7±18.6 pg/mL vs. 7.2×3.5 pg/mL, respectively, p0.05). The leptin concentration was well correlated with the BMI and %FM in the patients with chronic bronchitis and the leptin concentration was only correlated with the %FM (r=0.450, p=0.027) in emphysema patients. There was no correlation between the plasma leptin concentration, as adjusted for the fat mass, and the activity of the TNF-α system.
Conclusions
The interaction of leptin and the activity of the TNF-α system in the pathogenesis of tissue depletion may not play an important role in chronic stable COPD patients.
doi:10.3904/kjim.2007.22.4.249
PMCID: PMC2687660  PMID: 18309683
COPD; Weight loss; Leptin; Tumor necrosis factor-alpha
22.  Prevalence and correlations with depression, anxiety, and other features in outpatients with chronic obstructive pulmonary disease in China: a cross-sectional case control study 
Background
Patients with chronic obstructive pulmonary disease (COPD) often experience depression and anxiety, but little information is available regarding Chinese patients with these conditions. The present study assessed depression and anxiety in Chinese patients with COPD.
Methods
A case–controlled study was designed with 1100 patients with COPD enrolled in the case group and1100 residents without COPD and respiratory symptoms selected as the control group. Anxiety and depression in both groups were evaluated using the Hospital Anxiety and Depression Scale (HADS). The body mass index,degree of airflow obstruction, dyspnea, and exercise capacity (BODE ) index was used to assess COPD severity. Binary logistic regression models were used to test the association between anxiety and depression.
Results
The patients with COPD were more likely than controls to experience depression (cases, HADS 10.5 ± 3.6, prevalence 35.7%; controls, HADS 8.7 ± 2.7, prevalence 7.2%) and anxiety (cases, HADS 10.4 ± 3.1, prevalence 18.3%; controls, HADS 8.6 ± 2.1, prevalence 5.3%). Subjects with anxious and depressive symptoms had poorer health outcomes including a higher BODE index, a shorter 6-minute-walk distance (6MWD), more dyspnea, and a higher St George’s respiratory questionnaire (SGRQ) score. The prevalence of anxious and depressive symptoms increased with increasing BODE scores. On the basis of binary logistic regression, the BODE index was significantly correlated with anxiety (OR = 1.47, p < 0.001) and depression (OR = 1.51, p < 0.001). Anxious and depressive symptoms were also associated with several factors including younger age, female sex, higher education level, lower household income and history of smoking.
Conclusions
This study confirmed the high prevalence of anxiety and depression in Chinese outpatients with COPD. Patients with COPD who had anxiety and/or depression had a poorer health-related quality of life.
Trial registration
Chinese Clinical Trials Registration(ChiCTR-TRC-12001958)
doi:10.1186/1471-2466-12-53
PMCID: PMC3503755  PMID: 22958576
Chronic obstructive pulmonary disease; Anxiety; Depression; Hospital Anxiety and Depression Scale
23.  The impact of chronic obstructive pulmonary disease and obesity on length of stay and cost of spine surgery 
Indian Journal of Orthopaedics  2010;44(4):424-427.
Background:
Chronic obstructive pulmonary disease (COPD) and obesity may be more common among spine surgery patients than in the general population and may affect hospital cost.
Materials and Methods:
We retrospectively studied the prevalence of COPD and obesity among 605 randomly selected spine surgery inpatients operated between 2005 and 2008, including lumbar microdiskectomy, anterior cervical decompression and fusion and lumbar decompression and fusion patients. The length of hospital stay and hospital charges for patients with and without COPD and obesity (body mass index [BMI]≥30 kg/m2) were compared.
Results:
Among 605 spine surgery patients, 9.6% had a history of COPD. There were no statistical difference in the prevalence of COPD between the three spine surgery groups. Obesity was common, with 47.4% of the patients having a BMI≥30 kg/m2. There were no significant differences in obesity rates or BMI values between the three types of spine surgery patients. Obesity rates between patients with and without COPD were 62.1% vs. 45.9%, and were statistically different (P<0.05). Similarly, significant difference (P<0.01) in BMI values between COPD and non-COPD groups, 32.66±7.19 vs. 29.57±6.048 (mean ± std. deviation), was noted. There was significant difference (P<0.01) in cost between nonobese female patients without COPD and those with obesity and COPD in the anterior cervical decompression and fusion (ACDF) group. No association with increased hospital length of stay or cost was found in the other two types of spine surgery or in male ACDF patients.
Conclusion:
COPD and obesity seem to additively increase the length of hospital stay and hospital charges in ACDF female patients, an important finding that requires further investigation.
doi:10.4103/0019-5413.67120
PMCID: PMC2947730  PMID: 20924484
COPD; obesity; spine surgery; length of stay; hospital cost
24.  A Retrospective Analysis of Nutritional Parameters in Chronic Obstructive Pulmonary Disease between Sexes 
The aim of this study was to reveal the relationships between nutritional parameters and pulmonary functions in patients with chronic obstructive pulmonary disease (COPD) in both sexes. Spirometric, laboratory, and demographic data of 450 consecutive patients were analysed retrospectively. Males had significantly greater pack-years of smoking, more severe airway obstruction, and lower body mass index (BMI). In non-smokers, BMI was significantly lower in men independent of age and pulmonary functions. Creatine kinase levels showed no correlation with any pulmonary function parameters. Serum albumin levels correlated better than BMI with pulmonary functions. In conclusion, females with COPD were maintained weight better than men.
doi:10.3164/jcbn.2007024
PMCID: PMC2243246  PMID: 18299712
gender differences; lung diseases; obstructive; malnutrition; biomass
25.  Quantitative CT: Associations between Emphysema, Airway Wall Thickness and Body Composition in COPD 
Pulmonary Medicine  2011;2011:419328.
The objective of the present study was to determine the association between CT phenotypes—emphysema by low attenuation area and bronchitis by airway wall thickness—and body composition parameters in a large cohort of subjects with and without COPD. In 452 COPD subjects and 459 subjects without COPD, CT scans were performed to determine emphysema (%LAA), airway wall thickness (AWT-Pi10), and lung mass. Muscle wasting based on FFMI was assessed by bioelectrical impedance. In both the men and women with COPD, FFMI was negatively associated with %LAA. FMI was positively associated with AWT-Pi10 in both subjects with and without COPD. Among the subjects with muscle wasting, the percentage emphysema was high, but the predictive value was moderate. In conclusion, the present study strengthens the hypothesis that the subgroup of COPD cases with muscle wasting have emphysema. Airway wall thickness is positively associated with fat mass index in both subjects with and without COPD.
doi:10.1155/2011/419328
PMCID: PMC3100107  PMID: 21647214

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