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1.  Association of COPD candidate genes with CT emphysema and airway phenotypes in severe COPD 
The principal determining factors influencing the development of the airway disease and emphysema components of COPD have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway disease and emphysema. Therefore, we investigated genetic association of SNPs in COPD candidate genes for association with emphysema severity and airway wall thickness phenotypes.
Polymorphisms in six candidate genes were analyzed in 379 subjects of the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study with quantitative chest CT data. Genetic association with percent of lung below −950 hounsfield units (LAA950), airway wall thickness (WT), and derived square root wall area of 10 mm internal perimeter airways (SRWA) were investigated.
Three SNPs in EPHX1, five SNPs in SERPINE2, and one SNP in GSTP1 were significantly associated with LAA950. Five SNPs in TGFB1, two SNPs in EPHX1, one SNP in SERPINE2, and two SNPs in ADRB2 were associated with airway wall phenotypes in NETT.
In conclusion, several COPD candidate genes showed evidence for association with airway wall thickness and emphysema severity using CT in a severe COPD population. Further investigation will be required to replicate these genetic associations for emphysema and airway wall phenotypes.
PMCID: PMC3074301  PMID: 20525719
Airway; chronic obstructive pulmonary disease; computed tomography; emphysema; genetic association
2.  Involvement of surfactant protein D in emphysema revealed by genetic association study 
Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema.
Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed.
A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P=1.1 × 10−5) and overall LAA% (P=1.0 × 10−4), and negatively correlated with the serum concentration of SFTPD (P=7 × 10−11) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations.
Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema.
PMCID: PMC3260918  PMID: 21934714
chronic obstructive pulmonary disease; emphysema; genetic variation; pulmonary surfactant-associated protein D
3.  Relationships Between Airflow Obstruction and Quantitative CT Measurements of Emphysema, Air Trapping, and Airways in Subjects With and Without Chronic Obstructive Pulmonary Disease 
AJR. American journal of roentgenology  2013;201(3):W460-W470.
This study evaluates the relationships between quantitative CT (QCT) and spirometric measurements of disease severity in cigarette smokers with and without chronic obstructive pulmonary disease (COPD).
Inspiratory and expiratory CT scans of 4062 subjects in the Genetic Epidemiology of COPD (COPDGene) Study were evaluated. Measures examined included emphysema, defined as the percentage of low-attenuation areas ≤ −950 HU on inspiratory CT, which we refer to as “LAA-950I”; air trapping, defined as the percentage of low-attenuation areas ≤ −856 HU on expiratory CT, which we refer to as “LAA-856E”; and the inner diameter, inner and outer areas, wall area, airway wall thickness, and square root of the wall area of a hypothetical airway of 10-mm internal perimeter of segmental and subsegmental airways. Correlations were determined between spirometry and several QCT measures using statistics software (SAS, version 9.2).
QCT measurements of low-attenuation areas correlate strongly and significantly (p < 0.0001) with spirometry. The correlation between LAA-856E and forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) (r = −0.77 and −0.84, respectively) is stronger than the correlation between LAA-950I and FEV1 and FEV1/FVC (r = −0.67 and r = −0.76). Inspiratory and expiratory volume changes decreased with increasing disease severity, as measured by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) staging system (p < 0.0001). When airway variables were included with low-attenuation area measures in a multiple regression model, the model accounted for a statistically greater proportion of variation in FEV1 and FEV1/FVC (R2 = 0.72 and 0.77, respectively). Airway measurements alone are less correlated with spirometric measures of FEV1 (r = 0.15 to −0.44) and FEV1/FVC (r = 0.19 to −0.34).
QCT measurements are strongly associated with spirometric results showing impairment in smokers. LAA-856E strongly correlates with physiologic measurements of airway obstruction. Airway measurements can be used concurrently with QCT measures of low-attenuation areas to accurately predict lung function.
PMCID: PMC4067052  PMID: 23971478
air trapping; airway measurements; chronic obstructive pulmonary disease; emphysema; quantitative CT
4.  Body Composition in Severe Refractory Asthma: Comparison with COPD Patients and Healthy Smokers 
PLoS ONE  2010;5(10):e13233.
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.
PMCID: PMC2950851  PMID: 20949085
5.  Genome-Wide Association Analysis of Body Mass in Chronic Obstructive Pulmonary Disease 
Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity–associated (FTO) gene, and BMI (P = 4.97 × 10−7) and FFMI (P = 1.19 × 10−7). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10−3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.
PMCID: PMC3266061  PMID: 21037115
chronic obstructive pulmonary disease genetics; chronic obstructive pulmonary disease epidemiology; chronic obstructive pulmonary disease metabolism; genome-wide association study
6.  Relationship of Emphysema and Airway Disease Assessed by CT to Exercise Capacity in COPD 
Respiratory medicine  2010;104(8):1145-1151.
To assess the association of emphysema and airway disease assessed by volumetric computed tomography (CT) with exercise capacity in subjects with chronic obstructive pulmonary disease (COPD).
We studied 93 subjects with COPD (Forced Expiratory Volume in 1 s [FEV1] %predicted mean ± SD 57.1 ± 24.3%, female gender = 40) enrolled in the Lung Tissue Research Consortium. Emphysema was defined as percentage of low attenuation areas less than a threshold of −950 Hounsfield units (%LAA-950) on CT scan. The wall area percentage (WA%) of the 3rd to 6th generations of the apical bronchus of right upper lobe (RB1) were analyzed. The six-minute walk distance (6MWD) test was used as a measure of exercise capacity.
The 6MWD was inversely associated with %LAA-950 (r = −0.53, p<0.0001) and with the WA% of 6th generation of RB1 only (r = −0.28, p = 0.009). In a multivariate regression model including CT indices of emphysema and airway disease that were adjusted for demographic and physiologic variables as well as brand of CT scanner, only the %LAA-950 remained significantly associated with exercise performance. Holding other covariates fixed, this model showed that a 10% increase of CT emphysema reduced the distance walked in six minutes 28.6 meters (95% Confidence Interval = −51.2, −6.0, p = 0.01).
These results suggest that the extent of emphysema but not airway disease measured by volumetric CT contributes independently to exercise limitation in subjects with COPD.
PMCID: PMC2904840  PMID: 20385477
COPD; CT; emphysema; airways; 6-minute walk test
7.  TNF-α is associated with loss of lean body mass only in already cachectic COPD patients 
Respiratory Research  2012;13(1):48.
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.
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.
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.
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.
PMCID: PMC3487870  PMID: 22708547
Inflammation; TNF-α; COPD; Cachexia
8.  Association Between Emphysema Score, Six-Minute Walk and Cardiopulmonary Exercise Tests in COPD 
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.
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).
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.
These results suggest that COPD associated with emphysema on HRCT is characterized by more severe lung function impairment, greater exercise impairment and cardiopulmonary dysfunction.
PMCID: PMC3480708  PMID: 23115601
Chronic obstructive pulmonary disease; High-resolution computed tomography; Six-minute walk test; cardiopulmonary exercise test; Inspiratory capacity.
9.  Genetic Epidemiology of COPD (COPDGene) Study Design 
COPD  2010;7(1):32-43.
COPDGeneis a multicenter observational study designed to identify genetic factors associated with COPD. It will also characterize chest CT phenotypes in COPD subjects, including assessment of emphysema, gas trapping, and airway wall thickening. Finally, subtypes of COPD based on these phenotypes will be used in a comprehensive genome-wide study to identify COPD susceptibility genes.
COPDGene will enroll 10,000 smokers with and without COPD across the GOLD stages. Both Non-Hispanic white and African-American subjects are included in the cohort. Inspiratory and expiratory chest CT scans will be obtained on all participants. In addition to the cross-sectional enrollment process, these subjects will be followed regularly for longitudinal studies. A genome-wide association study (GWAS) will be done on an initial group of 4000 subjects to identify genetic variants associated with case-control status and several quantitative phenotypes related to COPD. The initial findings will be verified in an additional 2000 COPD cases and 2000 smoking control subjects, and further validation association studies will be carried out.
COPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans. Understanding genetic factors and CT phenotypes that define COPD will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
PMCID: PMC2924193  PMID: 20214461
10.  Relationship between Quantitative CT Metrics and Health Status and Bode in COPD 
Thorax  2012;67(5):399-406.
The value of quantitative computed tomography (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. We hypothesized that QCT-defined emphysema and airway abnormalities relate to St. George's Respiratory Questionnaire (SGRQ) and BODE.
1,200 COPDGene subjects meeting GOLD criteria for COPD with QCT analysis were included. Total lung emphysema was measured using density mask technique with a -950 HU threshold. An automated program measured mean wall thickness (WT), wall area percent (WA%) and pi10 in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
In separate models predicting SGRQ score, a one unit standard deviation (SD) increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a one unit SD increase in percent emphysema in these models was relatively weaker, significant only in the pi10 model (for percent emphysema, 1.45 points higher, p=0.01). In separate models predicting BODE, a one unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07 fold increase, p<0.001; for WA%, 1.20 fold increase, p<0.001; for pi10, 1.16 fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26 fold increase, p<0.001).
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
PMCID: PMC3719874  PMID: 22514236
Imaging; COPD; emphysema
11.  New Concepts in the Pathobiology of Chronic Obstructive Pulmonary Disease 
Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal persistent inflammatory response to cigarette smoke. This noxious insult leads to emphysema and airway remodeling, manifested by squamous and mucous metaplasia of the epithelium, smooth muscle hypertrophy, and airway wall fibrosis. These pathologic abnormalities interact synergistically to cause progressive airflow obstruction. Although it has been accepted that the spectrum of COPD is vast, the reasons for the development of different phenotypes from the same exposure to cigarette smoke have not been determined. Furthermore, it is becoming increasingly clear that airways disease and emphysema often coexist in many patients, even with a clear clinical phenotype of either emphysema or chronic bronchitis. Recent studies have focused on the nature of the inflammatory response to cigarette smoke, the inflammatory cell lines responsible for COPD pathogenesis, and new biomarkers for disease activity and progression. New cytokines are being discovered, and the complex interactions among them are being unraveled. The inflammatory biomarker that has received the most attention is C-reactive protein, but new ones that have caught our attention are interleukin (IL)-6, tumor necrosis factor-α, IL-8, and IL-10. Further research should focus on how these new concepts in lung inflammation interact to cause the various aspects of COPD pathology.
PMCID: PMC2645323  PMID: 18453359
chronic obstructive pulmonary disease; pathology; airway inflammation; emphysema; inflammatory biomarkers
COPD  2010;7(4):262-268.
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes.
We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1) and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n=389) and smoking controls from the Normative Aging Study (NAS, n=472). We examined whether the SNPs were associated with COPD status, lung function variables, and quantitative CT measurements of emphysema and airway wall thickness. Further, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n=3061) and the Boston Early-Onset COPD Study (EOCOPD, n=949).
In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p=0.029 and p=0.0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p=0.048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations.
In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
PMCID: PMC2923920  PMID: 20673035
13.  A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK 
Genome Medicine  2012;4(8):67.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time.
In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans.
We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGFβ) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGFβ pathway activation. Treatment of human fibroblasts with GHK recapitulated TGFβ-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin β1. Furthermore, addition of GHK or TGFβ restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD.
These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual's lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGFβ and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.
PMCID: PMC4064320  PMID: 22937864
14.  Association between markers of emphysema and more severe chronic obstructive pulmonary disease 
Thorax  2006;61(12):1037-1042.
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.
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.
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).
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.
PMCID: PMC2117071  PMID: 16769715
chronic obstructive pulmonary disease; emphysema; biological markers; outcomes
15.  Gender Differences in Relationship between Fat-Free Mass Index and Fat Mass Index among Korean Children Using Body Composition Chart 
Yonsei Medical Journal  2011;52(6):948-952.
This study aimed to investigate gender differences in the relationship between fat-free mass index (FFMI) and fat mass index (FMI) by applying body composition chart on Korean elementary students.
Materials and Methods
Data from 965 healthy Korean children of 8 to 12 years of age (501 boys, 464 girls) were obtained. FFMI and FMI were plotted on the body composition chart, and the differences in the relationships between FFMI and FMI were separately evaluated by gender or grade.
Weight was heavier and BMI was higher in 3rd and 4th grade boys compare to girls. The value of FFM was higher in boys, but FM was not different. In subgroup analysis by grade, significant gender by FFMI interaction (p=0.015) was found, indicating that the slope of the lines for FMI vs. FFMI was different between boys and girls (Figure was not shown). In subgroup analysis by gender, grade by FFMI interaction was significant in boys, indicating that FMI vs. FFMI relationship differed according to grade only in boys.
Boys are leaner than girls, despite having similar BMI. Gender difference in the direction of the change of the FFMI and FMI relationship is evident in children.
PMCID: PMC3220241  PMID: 22028158
Obesity; child; Korea
16.  Low-dose CT measurements of airway dimensions and emphysema associated with airflow limitation in heavy smokers: a cross sectional study 
Respiratory Research  2013;14(1):11.
Increased airway wall thickness (AWT) and parenchymal lung destruction both contribute to airflow limitation. Advances in computed tomography (CT) post-processing imaging allow to quantify these features. The aim of this Dutch population study is to assess the relationships between AWT, lung function, emphysema and respiratory symptoms.
AWT and emphysema were assessed by low-dose CT in 500 male heavy smokers, randomly selected from a lung cancer screening population. AWT was measured in each lung lobe in cross-sectionally reformatted images with an automated imaging program at locations with an internal diameter of 3.5 mm, and validated in smaller cohorts of patients. The 15th percentile method (Perc15) was used to assess the severity of emphysema. Information about respiratory symptoms and smoking behavior was collected by questionnaires and lung function by spirometry.
Median AWT in airways with an internal diameter of 3.5 mm (AWT3.5) was 0.57 (0.44 - 0.74) mm. Median AWT in subjects without symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/or wheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysis only AWT3.5 and emphysema independently explained 31.1%and 9.5%of the variance in FEV1%predicted, respectively, after adjustment for smoking behavior.
Post processing standardization of airway wall measurements provides a reliable and useful method to assess airway wall thickness. Increased airway wall thickness contributes more to airflow limitation than emphysema in a smoking male population even after adjustment for smoking behavior.
PMCID: PMC3570364  PMID: 23356533
Airway dimensions; Low-dose CT; Respiratory symptoms; Smoking; Airflow limitation; Emphysema
17.  Sex Differences in Severe Pulmonary Emphysema 
Rationale: Limited data on sex differences in advanced COPD are available.
Objectives: To compare male and female emphysema patients with severe disease.
Methods: One thousand fifty-three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National Emphysema Treatment Trial were analyzed.
Measurements and Main Results: Detailed clinical, physiological, and radiological assessment, including quantitation of emphysema severity and distribution from helical chest computed tomography, was completed. In a subgroup (n = 101), airway size and thickness was determined by histological analyses of resected tissue. Women were younger and exhibited a lower body mass index (BMI), shorter smoking history, less severe airflow obstruction, lower Dlco and arterial Po2, higher arterial Pco2, shorter six-minute walk distance, and lower maximal wattage during oxygen-supplemented cycle ergometry. For a given FEV1% predicted, age, number of pack-years, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE, more depression, lower SF-36 mental component score, and lower quality of well-being. Overall emphysema was less severe in women, with the difference from men most evident in the outer peel of the lung. Females had thicker small airway walls relative to luminal perimeters.
Conclusions: In patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.
PMCID: PMC1994221  PMID: 17431226
chronic obstructive pulmonary disease; emphysema; computed tomography; pulmonary function; gender
18.  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.
PMCID: PMC3504379  PMID: 23209935
19.  Convergence of the epidemiology and pathology of COPD 
Thorax  2006;61(1):86-88.
The epidemiology of chronic obstructive pulmonary disease (COPD) has been dominated by one hypothesis stating that cigarette smoking and chronic bronchitis were the key to pathogenesis and another that asthma, chronic bronchitis, and even emphysema are related to different expressions of a primary airway abnormality. The first hypothesis was rejected in the late 1960s based on a longitudinal study of working men where only a fraction of smokers developed COPD and where development of COPD was independent of the absence or presence of chronic bronchitis. Chronic bronchitis in more advanced COPD was subsequently associated with a more rapid decline in lung function and more frequent exacerbations. The second hypothesis is more difficult to test but longitudinal studies have shown that the presence of bronchial hyperresponsiveness may predict the subjects who go on to develop COPD. This brief review attempts to reconcile these findings with the pathology found in the lung.
PMCID: PMC2080699  PMID: 16227325
chronic obstructive pulmonary disease; pathology; epidemiology; smoking; pathogenesis
20.  Fat-free mass index: changes and race/ethnic differences in adulthood 
Nutritional status is assessed by measuring BMI or percent body fat (%fat). BMI can misclassify persons who carry more weight as fat-free mass and %fat can be misleading in cases of malnutrition or in disease states characterized by wasting of lean tissue. The fat-free mass index (FFMI) is proposed to assess body composition in individuals who have a similar body composition but differ in height allowing identification of those suffering from malnutrition, wasting or those that possess a relatively high muscle mass. The purpose was to determine whether the FFMI differs in a group of racially/ethnically diverse adults.
Subjects were a multi-ethnic sample (Caucasian, CA; African American, AA; Hispanic, HIS and Asian, AS) of 1339 healthy males (n = 480) and females (n = 859) ranging in age from 18–110 years. Total body fat, total fat-free mass and bone mineral density were estimated using dual energy X-ray absorptiometry.
FFMI differed among the four ethnic groups (P ≤ 0.05) for both genders. A curvilinear relationship was found between age and FFMI for both genders although the coefficients in the quadratic model differed between genders (P ≤ 0.001) indicating the rate of change in FFMI differed between genders. The estimated turning point where FFMI started to decline was in the mid 20s for male and mid 40s for female participants. An age × gender interaction was found such that the rate of decline was greater in male than female participants (P ≤ 0.001). For both genders, FFMI was greatest in AA and the least in AS (P ≤ 0.001). There was no significant interaction between race and age or age2 (P = 0.06). However, male participants consistently had a greater FFMI than female participants (P ≤ 0.001).
These findings have clinical implications for identifying individuals who may not be recognized as being malnourished based on their BMI or %fat but whose fat-free mass corrected for height is relatively low.
PMCID: PMC3306818  PMID: 20531353
fat-free mass index; fat-free mass; body mass index (BMI); percent body fat; nutritional assessment
21.  Analyses of body composition charts among younger and older Chinese children and adolescents aged 5 to 18 years 
BMC Public Health  2012;12:835.
Childhood obesity has become a major public health problem in China. The objective of this study was to examine the effect of age and sex on the relationship between fat-free mass (FFM) and fat mass (FM), fat-free mass index (FFMI) and fat mass index (FMI) in Chinese children using body composition chart analysis, and to compare the changing pattern with Caucasian and Japanese counterparts.
A total of 1458 children (790 boys and 668 girls) between 5 and 18 years of age were studied to determine a body composition by bioelectrical impedance analysis. The relationship of FFM and FM, FFMI and FMI were delineated by body composition charts.
Different changing patterns in body composition were observed during 5-11y (younger age group), and 12-18y (older age group), with non-significant sex difference with FM and FMI for the younger age group and significant sex and age differences for the older age group. For the younger age group, simultaneous increase of FFM and FM was found in both genders. However, for the older age group, the increase in weight and BMI with age is largely due to the increment of FFM and FFMI in boys, and of FM and FMI in girls. In addition, different changing patterns in body composition exist between Chinese children and their Caucasian and Japanese counterparts, largely due to the higher fat mass component in Chinese subjects.
Our results indicate that age- and gender-related changing patterns of body composition in Chinese children may differ at different growth stage, and differ with those in Caucasian and Japanese children at the same age period. Such changing patterns should be considered when designing the intervention proposal for childhood obesity in China.
PMCID: PMC3548758  PMID: 23025289
Body composition chart; Body mass index; Fat-free mass index; Fat mass index; Chinese children
22.  Polyunsaturated fatty acids improve exercise capacity in chronic obstructive pulmonary disease 
Thorax  2005;60(5):376-382.
Background: Muscle wasting and decreased muscle oxidative capacity commonly occur in patients with chronic obstructive pulmonary disease (COPD). Polyunsaturated fatty acids (PUFA) have been shown to mediate several inflammatory and metabolic pathways which may be involved in the pathogenesis of muscle impairment in COPD. The aim of this study was to investigate the effect of PUFA modulation on systemic inflammation, reversal of muscle wasting, and functional status in COPD.
Methods: Eighty patients with COPD (57 men) with forced expiratory volume in 1 second (FEV1) 37.3 (13.8)% predicted received 9 g PUFA or placebo daily in a double blind randomised fashion during an 8 week rehabilitation programme. Body composition (bioelectrical impedance), functional capacity (lung function, incremental cycle ergometry test, submaximal cycle test, isokinetic quadriceps strength) and inflammatory markers (C-reactive protein (CRP), interleukin (IL)-6 and tumour necrosis factor (TNF)-α) were assessed at baseline and after 8 weeks.
Results: Both groups had similar increases in weight, fat-free mass (FFM), and muscle strength. The peak load of the incremental exercise test increased more in the PUFA group than in the placebo group (difference in increase 9.7 W (95% CI 2.5 to 17.0), p = 0.009) even after adjustment for FFM. The duration of the constant work rate test also increased more in patients receiving PUFA (difference in increase 4.3 min (95% CI 0.6 to 7.9), p = 0.023). The positive effects of PUFA could not be attributed to a decrease in systemic levels of CRP, IL-6 and TNF-α.
Conclusions: This is the first study to show beneficial effects of PUFA on exercise capacity in patients with COPD.
PMCID: PMC1758900  PMID: 15860712
23.  Increased Cytokine Response of Rhinovirus-infected Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease 
Rationale: Airway inflammation is a central feature of chronic obstructive pulmonary disease (COPD). COPD exacerbations are often triggered by rhinovirus (RV) infection.
Objectives: We hypothesized that airway epithelial cells from patients with COPD maintain a proinflammatory phenotype compared with control subjects, leading to greater RV responses.
Methods: Cells were isolated from tracheobronchial tissues of 12 patients with COPD and 10 transplant donors. Eight patients with COPD had severe emphysema, three had mild to moderate emphysema, and one had no emphysema. All had moderate to severe airflow obstruction, and six met criteria for chronic bronchitis or had at least one exacerbation the previous year. Cells were grown at air–liquid interface and infected with RV serotype 39. Cytokine and IFN expression was measured by ELISA. Selected genes involved in inflammation, oxidative stress, and proteolysis were assessed by focused gene array and real-time polymerase chain reaction.
Measurements and Main Results: Compared with control subjects, cells from patients with COPD demonstrated increased mRNA expression of genes involved in oxidative stress and the response to viral infection, including NOX1, DUOXA2, MMP12, ICAM1, DDX58/RIG-I, STAT1, and STAT2. COPD cells showed elevated baseline and RV-stimulated protein levels of IL-6, IL-8/CXCL8, and growth-related oncogene-α/CXCL1. COPD cells demonstrated increased viral titer and copy number after RV infection, despite increased IL-29/IFN-λ1, IL-28A/IFN-λ2, and IFN-inducible protein-10/CXCL10 protein levels. Finally, RV-infected COPD cultures showed increased mRNA expression of IL28A/IFNλ2, IL29/IFNλ1, IFIH1/MDA5, DDX58/RIG-I, DUOX1, DUOX2, IRF7, STAT1, and STAT2.
Conclusions: Airway epithelial cells from patients with COPD show higher baseline levels of cytokine expression and increased susceptibility to RV infection, despite an increased IFN response.
PMCID: PMC2921598  PMID: 20395558
C-X-C chemokine; IL-6; IFN; NOX1; retinoic acid inducible gene–I
24.  Can a normal peak expiratory flow exclude severe chronic obstructive pulmonary disease? 
Chronic obstructive pulmonary disease (COPD) is underdiagnosed. One barrier to diagnosis is the limited availability of spirometry testing, but in adults at risk for COPD, a normal pre-bronchodilator (pre-BD) peak expiratory flow (PEF) may rule out clinically significant COPD.
To identify post-BD airway obstruction using data from 13 708 individuals aged ≥40 years from the PLATINO and BOLD studies.
We evaluated different cut-off points of pre-BD. The PEF was obtained from a diagnostic-quality spirometer (not a mechanical PEF meter). At least one of the following COPD risk factors was present in 77% of the subjects: chronic respiratory symptoms; exposure to tobacco smoke, biomass smoke or dust in the workplace; or a previous diagnosis of asthma, COPD, emphysema or chronic bronchitis.
Although the positive predictive value was low as expected, a pre-BD PEF of ≥70% predicted effectively ruled out Stages III and IV COPD of the Global Initiative for Chronic Obstructive Lung Disease. Among those with at least one risk factor, only 12% would require confirmatory spirometry using this criterion.
Adding PEF measurement to a screening questionnaire may rule out severe to very severe COPD without the need for pre- and post-BD spirometry testing. Confirmation is needed from a study using inexpensive PEF meters or pocket spirometers with a staged screening protocol.
PMCID: PMC3334276  PMID: 19275802
25.  Longitudinal Study of Spatially Heterogeneous Emphysema Progression in Current Smokers with Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(9):e44993.
Cigarette smoke is the main risk factor for emphysema, which is a key pathology in chronic obstructive pulmonary disease (COPD). Low attenuation areas (LAA) in computed tomography (CT) images reflect emphysema, and the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D. This property of LAA clusters can be explained by model simulation, where mechanical force breaks alveolar walls causing local heterogeneous lung tissue destruction. However, a longitudinal CT study has not investigated whether continuous smoking causes the spatially heterogeneous progression of emphysema.
We measured annual changes in ratios of LAA (LAA%), D and numbers of LAA clusters (LAN) in CT images acquired at intervals of ≥3 years from 22 current and 31 former smokers with COPD to assess emphysema progression. We constructed model simulations using CT images to morphologically interpret changes in current smokers.
D was decreased in current and former smokers, whereas LAA% and LAN were increased only in current smokers. The annual changes in LAA%, D, and LAN were greater in current, than in former smokers (1.03 vs. 0.37%, p = 0.008; −0.045 vs. −0.01, p = 0.004; 13.9 vs. 1.1, p = 0.007, respectively). When LAA% increased in model simulations, the coalescence of neighboring LAA clusters decreased D, but the combination of changes in D and LAN in current smokers could not be explained by the homogeneous emphysema progression model despite cluster coalescence. Conversely, a model in which LAAs heterogeneously increased and LAA clusters merged somewhat in relatively advanced emphysematous regions could reflect actual changes.
Susceptibility to parenchymal destruction induced by continuous smoking is not uniform over the lung, but might be higher in local regions of relatively advanced emphysema. These could result in the spatially heterogeneous progression of emphysema in current smokers.
PMCID: PMC3445600  PMID: 23028728

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