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1.  Bacterial microbiome of lungs in COPD 
Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death in the world. Although smoking is the main risk factor for this disease, only a minority of smokers develop COPD. Why this happens is largely unknown. Recent discoveries by the human microbiome project have shed new light on the importance and richness of the bacterial microbiota at different body sites in human beings. The microbiota plays a particularly important role in the development and functional integrity of the immune system. Shifts or perturbations in the microbiota can lead to disease. COPD is in part mediated by dysregulated immune responses to cigarette smoke and other environmental insults. Although traditionally the lung has been viewed as a sterile organ, by using highly sensitive genomic techniques, recent reports have identified diverse bacterial communities in the human lung that may change in COPD. This review summarizes the current knowledge concerning the lung microbiota in COPD and its potential implications for pathogenesis of the disease.
PMCID: PMC3937108  PMID: 24591822
chronic obstructive pulmonary disease; bacterial microbiome; lungs
2.  Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD 
Human genetics  2012;132(1):79-90.
Accelerated lung function decline is a key COPD phenotype; however its genetic control remains largely unknown.
We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European-American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry.
Measurements and Main Results
Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status.
We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
PMCID: PMC3536920  PMID: 22986903
COPD; lung function decline; GWAS; genome wide association; genes; polymorphisms
4.  Budesonide/Formoterol Enhances the Expression of Pro Surfactant Protein-B in Lungs of COPD Patients 
PLoS ONE  2013;8(12):e83881.
Rationale & Aim
Pulmonary surfactants are essential components of lung homeostasis. In chronic obstructive pulmonary disease (COPD), surfactant expression decreases in lungs whereas, there is a paradoxical increase in protein expression in plasma. The latter has been associated with poor health outcomes in COPD. The purpose of this study was to determine the relationship of surfactants and other pneumoproteins in bronchoalveolar lavage (BAL) fluid and plasma to airflow limitation and the effects of budesonide/formoterol on this relationship.
We recruited (clinical identifier: NCT00569712) 7 smokers without COPD and 30 ex and current smokers with COPD who were free of exacerbations for at least 4 weeks. All subjects were treated with budesonide/formoterol 400/12 µg twice a day for 4 weeks. BAL fluid and plasma samples were obtained at baseline and the end of the 4 weeks. We measured lung-predominant pneumoproteins: pro-Surfactant Protein-B (pro-SFTPB), Surfactant Protein-D (SP-D), Club Cell Secretory Protein-16 (CCSP-16) and Pulmonary and Activation-Regulated Chemokine (PARC/CCL-18) in BAL fluid and plasma.
BAL Pro-SFTPB concentrations had the strongest relationship with airflow limitation as measured by FEV1/FVC (Spearman rho = 0.509; p = 0.001) and FEV1% of predicted (Spearman rho =  0.362; p = 0.028). Plasma CCSP-16 concentrations were also significantly related to airflow limitation (Spearman rho = 0.362; p = 0.028 for FEV1% of predicted). The other biomarkers in BAL fluid or plasma were not significantly associated with airflow limitation. In COPD subjects, budesonide/formoterol significantly increased the BAL concentrations of pro-SFTPB by a median of 62.46 ng/ml (p = 0.022) or 48.7% from baseline median value.
Increased severity of COPD is associated with reduced Pro-SFTPB levels in BAL fluid. Short-term treatment with budesonide/formoterol increases these levels in BAL fluid. Long term studies will be needed to determine the clinical relevance of this observation.
PMCID: PMC3873417  PMID: 24386300
5.  Aging does not Enhance Experimental Cigarette Smoke-Induced COPD in the Mouse 
PLoS ONE  2013;8(8):e71410.
It has been proposed that the development of COPD is driven by premature aging/premature senescence of lung parenchyma cells. There are data suggesting that old mice develop a greater inflammatory and lower anti-oxidant response after cigarette smoke compared to young mice, but whether these differences actually translate into greater levels of disease is unknown. We exposed C57Bl/6 female mice to daily cigarette smoke for 6 months starting at age 3 months (Ayoung@) or age 12 months (Aold@), with air-exposed controls. There were no differences in measures of airspace size between the two control groups and cigarette smoke induced exactly the same amount of emphysema in young and old. The severity of smoke-induced small airway remodeling using various measures was identical in both groups. Smoke increased numbers of tissue macrophages and neutrophils and levels of 8-hydroxyguanosine, a marker of oxidant damage, but there were no differences between young and old. Gene expression studies using laser capture microdissected airways and parenchyma overall showed a trend to lower levels in older animals and a somewhat lesser response to cigarette smoke in both airways and parenchyma but the differences were usually not marked. Telomere length was greatest in young control mice and was decreased by both smoking and age. The senescence marker p21Waf1 was equally upregulated by smoke in young and old, but p16INK4a, another senescence marker, was not upregulated at all. We conclude, in this model, animal age does not affect the development of emphysema and small airway remodeling.
PMCID: PMC3732225  PMID: 23936505
6.  Improved patient outcome with smoking cessation: when is it too late? 
Smoking is the leading modifiable risk factor for chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and lung cancer. Smoking cessation is the only proven way of modifying the natural course of COPD. It is also the most effective way of reducing the risk for myocardial infarction and lung cancer. However, the full benefits of tobacco treatment may not be realized until many years of abstinence. All patients with COPD, regardless of severity, appear to benefit from tobacco treatment. Similarly, patients with recent CVD events also benefit from tobacco treatment. The risk of total mortality and rate of recurrence of lung cancer is substantially lower in smokers who manage to quit smoking following the diagnosis of early stage lung cancer or small cell lung cancer. Together, these data suggest that tobacco treatment is effective both as a primary and a secondary intervention in reducing total morbidity and mortality related to COPD, CVD, and lung cancer. In this paper, we summarize the evidence for tobacco treatment and the methods by which smoking cessation can be promoted in smokers with lung disease.
PMCID: PMC3144846  PMID: 21814462
COPD; lung cancer; tobacco treatment; smoking cessation
7.  The Lung Tissue Microbiome in Chronic Obstructive Pulmonary Disease 
Rationale: Based on surface brushings and bronchoalveolar lavage fluid, Hilty and coworkers demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), which have now been confirmed by others.
Objectives: To extend these findings to human lung tissue samples.
Methods: DNA from lung tissue samples was obtained from nonsmokers (n = 8); smokers without COPD (n = 8); patients with very severe COPD (Global Initiative for COPD [GOLD] 4) (n = 8); and patients with cystic fibrosis (CF) (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying 16S rRNA gene fragments. Total bacterial populations were measured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing.
Measurement and Main Results: Total bacterial populations within lung tissue were small (20–1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P < 0.001). Terminal restriction fragment length polymorphism analysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, a second to the GOLD 4 group, and the third to the CF-positive control group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007).
Conclusions: There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD.
PMCID: PMC3359894  PMID: 22427533
COPD; bacteria; microbiome
9.  Treatment of mild chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is an epidemic in many parts of the world. Most patients with COPD demonstrate mild disease. The cornerstone of management of mild disease is smoking cessation, which is the only proven intervention to relieve symptoms, modify its natural history and reduce mortality. For asymptomatic patients, it is the only required therapy. Short-acting bronchodilators can be added on an as needed basis for those with intermittent symptoms and regularly for those with persistent symptoms. Long-acting bronchodilators can be substituted for those who remain symptomatic despite regular use of short-acting bronchodilators. Inhaled corticosteroids do not modify the natural history of COPD and as such cannot be recommended as standalone therapy for mild COPD. However, for patients with refractory and intractable symptoms, they may be used in combination with long-acting beta-2 agonists. Influenza and pneumococcal vaccination and pulmonary rehabilitation are other therapies that may be considered for select patients with mild disease. In this paper, we summarize the current standard of care for patients with mild COPD.
PMCID: PMC2650603  PMID: 19281074
COPD; management; mild COPD
10.  Lung inflammation in COPD: why does it matter? 
COPD is characterized by lung inflammation, which intensifies with disease progression. Recent studies suggest that COPD has multiple phenotypes, each with a distinct molecular pathway. Proteolytic enzymes may have a prominent role in the emphysematous phenotype, while nitric oxide pathways may be more relevant for pulmonary vessel remodelling in COPD. This article provides a synopsis of the possible role that lung inflammation plays in the pathogenesis of COPD.
PMCID: PMC3516832  PMID: 23236338
11.  Effects of inhaled corticosteroids on airway inflammation in chronic obstructive pulmonary disease: a systematic review and meta-analysis 
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in the small airways. The effect of inhaled corticosteroids (ICS) on lung inflammation in COPD remains uncertain. We sought to determine the effects of ICS on inflammatory indices in bronchial biopsies and bronchoalveolar lavage fluid of patients with COPD.
We searched Medline, Embase, Cinahl, and the Cochrane database for randomized, controlled clinical trials that used bronchial biopsies and bronchoalveolar lavage to evaluate the effects of ICS in stable COPD. For each chosen study, we calculated the mean differences in the concentrations of inflammatory cells before and after treatment in both intervention and control groups. These values were then converted into standardized mean differences (SMD) to accommodate the differences in patient selection, clinical treatment, and biochemical procedures that were employed across the original studies. If significant heterogeneity was present (P < 0.1), then a random effects model was used to pool the original data; otherwise, a fixed effects model was used.
We identified eight original studies that met the inclusion criteria. Four studies used bronchial biopsies (n =102 participants) and showed that ICS were effective in reducing CD4 and CD8 cell counts (SMD, −0.52 units and −0.66 units, 95% confidence interval). The five studies used bronchoalveolar lavage fluid (n =309), which together showed that ICS reduced neutrophil and lymphocyte counts (SMD, −0.64 units and −0.64 units, 95% confidence interval). ICS on the other hand significantly increased macrophage counts (SMD, 0.68 units, 95% confidence interval) in bronchoalveolar lavage fluid.
ICS has important immunomodulatory effects in airways with COPD that may explain its beneficial effect on exacerbations and enhanced risk of pneumonia.
PMCID: PMC3459653  PMID: 23055709
chronic obstructive pulmonary disease; bronchial biopsies; bronchoalveolar lavage; inhaled corticosteroids; inflammation; inflammatory markers; meta-analysis
12.  SP-D Polymorphisms and the Risk of COPD 
Disease markers  2012;33(2):91-100.
Introduction: There are limited data linking serum levels of surfactant protein D, its genetic polymorphisms to the risk of Chronic Obstructive Pulmonary Disease (COPD). Objectives: We sought to investigate these relationships using a case control study design.
Methods: Post bronchodilator values of FEV1/FVC <0.7 were used to diagnose COPD patients (n = 115). Controls were healthy subjects with normal spirometry (n = 106) Single nucleotide polymorphisms (rs721917, rs2243639, rs3088308) were genotyped using polymerase chain reaction (PCR) and restriction analysis. Serum SP-D levels were measured using a specific immunoassay.
Results: Allele ‘A’ at rs3088308 (p < 0.00, B = −0.41) and ‘C’ allele at rs721917 (p = 0.03; B = −0.30) were associated with reduced serum SP-D levels. Genotype ‘T/T’ at rs721917 was significantly associated with risk of COPD (p = 0.01). Patients with repeat exacerbations had significantly higher serum SP-D even after adjusting for genetic factors.
Conclusions: We report for the first time that rs3088308 is an important factor influencing systemic SP-D levels and confirm the previous association of rs721917 to the risk of COPD and serum SP-D levels.
PMCID: PMC3810685  PMID: 22846212
Surfactant protein D; SP-D SNPs; serum SP-D levels; COPD risk; SP-D haplotypes
13.  Serum PARC/CCL-18 Concentrations and Health Outcomes in Chronic Obstructive Pulmonary Disease 
Rationale: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum.
Objectives: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality.
Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study.
Measurements and Main Results: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort.
Conclusions: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.
Clinical trial registered with (NCT 00292552).
PMCID: PMC3114051  PMID: 21216880
biomarker; chronic obstructive pulmonary disease; PARC/CCL-18; chemokine
14.  The Relationship between Telomere Length and Mortality in Chronic Obstructive Pulmonary Disease (COPD) 
PLoS ONE  2012;7(4):e35567.
Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV1 and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy “mid-life” volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy “mid-life” volunteers (p<.001). Compared to individuals in the 4th quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.
PMCID: PMC3338848  PMID: 22558169
15.  The relationship of systemic inflammation to prior hospitalization in adult patients with cystic fibrosis 
In cystic fibrosis (CF) patients, it has been suggested that systemic inflammation may be an important risk factor for poor health outcomes. The relationship of plasma inflammatory biomarkers to lung function and hospitalization history remains largely unexplored.
This cross-sectional study included 58 consecutive, clinically stable adults from the CF Clinic at St. Paul's Hospital (Vancouver, Canada). Blood levels of interleukin (IL)-6, IL-1β, C-reactive protein (CRP), interleukin (IL)-6, IL-1β, granzyme B (GzmB), chemokine C-C motif ligand 18 (CCL18/PARC), surfactant protein D (SP-D), lipopolysaccharide (LPS)-binding protein, and soluble cluster of differentiation 14 (sCD14) were measured using enzyme-linked immunosorbent assays, and LPS levels were measured using a Limulus amebocyte lysate assay. Spirometry was also performed. Multivariable linear regression analysis was used to assess relationships of the blood biomarkers to lung function.
Lung function impairment was independently associated with elevated plasma levels of CRP (P < 0.01), IL-6 (P = 0.04), IL-1β (P < 0.01), and LBP (P < 0.01). Increasing age (P < 0.01), reduced body mass index (P = 0.02), prior hospitalizations (P = 0.03), and presence of Pseudomonas aeruginosa in sputum cultures (P < 0.01) were also associated with reduced lung function. Elevated concentrations of LPS in plasma were associated with a previous history of hospitalization (P < 0.05). There was a trend towards an increase in plasma IL-6 (P = 0.07) and IL-1β (P = 0.06) levels in patients who were previously hospitalized.
IL-6 and IL-1β are promising systemic biomarkers for lung function impairment and history of hospitalization in adult patients with CF.
PMCID: PMC3312864  PMID: 22333132
16.  The role of female hormones on lung function in chronic lung diseases 
BMC Women's Health  2011;11:24.
The prevalence, morbidity, and mortality of inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are increasing in women. There is a dearth of data on the biological mechanisms to explain such observations. However, some large epidemiologic studies suggest that lung function fluctuates during the menstrual cycle in female patients with airways disease but not in women without disease, suggesting that circulating estradiol and progesterone may be involved in this process.
In asthma, estradiol shuttles adaptive immunity towards the TH2 phenotype while in smokers estrogens may be involved in the generation of toxic intermediate metabolites in the airways of female smokers, which may be relevant in COPD pathogenesis. In CF, estradiol has been demonstrated to up-regulate MUC5B gene in human airway epithelial cells and inhibit chloride secretion in the airways. Progesterone may augment airway inflammation.
Taken together, clinical and in-vivo data have demonstrated a sex-related difference in that females may be more susceptible to the pathogenesis of lung diseases. In this paper, we review the effect of female sex hormones in the context of these inflammatory airway diseases.
PMCID: PMC3129308  PMID: 21639909
lung function; menstrual cycle; sex hormones; asthma; cystic fibrosis; COPD
17.  Effect of gene environment interactions on lung function and cardiovascular disease in COPD 
The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-γ (IFNG), interleukin-1β (IL1B), or interleukin-1 receptor antagonist (IL1RN) single nucleotide polymorphisms are associated with lung function decline and cardiovascular disease in chronic obstructive pulmonary disease (COPD).
Single nucleotide polymorphisms (SNPs) in IL6, IFNG, IL1B, and IL1RN were genotyped in the Lung Health Study and correlated with rate of decline of forced expiratory volume in 1 second (FEV1) over 5 years, baseline FEV1, serum protein levels, cardiovascular disease, and interactions with smoking.
The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV1 (P = 0.049), and was found to have a significant interaction (P = 0.004) with mean number of cigarettes smoked per day. There was also a significant interaction of IFNG rs2069727 with smoking on prebronchodilator (P = 0.008) and postbronchodilator (P =0.01) FEV1. The IL6 polymorphism was also associated with cardiovascular disease in heterozygous individuals (P = 0.044), and was found to have a significant interaction with smoking (P = 0.024). None of the genetic variants were associated with their respective serum protein levels.
The results suggest interactions of IL6 rs2069825 and IFNG rs2069727 single nucleotide polymorphisms with cigarette smoking on measures of lung function. The IL6 rs2069825 single nucleotide polymorphism also interacted with smoking to affect the risk of cardiovascular disease in COPD patients.
PMCID: PMC3144847  PMID: 21814463
gene-environment interactions; interleukin-6; forced expiratory volume in one second; cardiovascular disease; chronic obstructive pulmonary disease
18.  Quantification of lung surface area using computed tomography 
Respiratory Research  2010;11(1):153.
To refine the CT prediction of emphysema by comparing histology and CT for specific regions of lung. To incorporate both regional lung density measured by CT and cluster analysis of low attenuation areas for comparison with histological measurement of surface area per unit lung volume.
The histological surface area per unit lung volume was estimated for 140 samples taken from resected lung specimens of fourteen subjects. The region of the lung sampled for histology was located on the pre-operative CT scan; the regional CT median lung density and emphysematous lesion size were calculated using the X-ray attenuation values and a low attenuation cluster analysis. Linear mixed models were used to examine the relationships between histological surface area per unit lung volume and CT measures.
The median CT lung density, low attenuation cluster analysis, and the combination of both were important predictors of surface area per unit lung volume measured by histology (p < 0.0001). Akaike's information criterion showed the model incorporating both parameters provided the most accurate prediction of emphysema.
Combining CT measures of lung density and emphysematous lesion size provides a more accurate estimate of lung surface area per unit lung volume than either measure alone.
PMCID: PMC2976969  PMID: 21040527
19.  Connective Tissue-Activating Peptide III: A Novel Blood Biomarker for Early Lung Cancer Detection 
Journal of Clinical Oncology  2009;27(17):2787-2792.
There are no reliable blood biomarkers to detect early lung cancer. We used a novel strategy that allows discovery of differentially present proteins against a complex and variable background.
Mass spectrometry analyses of paired pulmonary venous-radial arterial blood from 16 lung cancer patients were applied to identify plasma proteins potentially derived from the tumor microenvironment. Two differentially expressed proteins were confirmed in 64 paired venous-arterial blood samples using an immunoassay. Twenty-eight pre- and postsurgical resection peripheral blood samples and two independent, blinded sets of plasma from 149 participants in a lung cancer screening study (49 lung cancers and 100 controls) and 266 participants from the National Heart Lung and Blood Institute Lung Health Study (45 lung cancer and 221 matched controls) determined the accuracy of the two protein markers to detect subclinical lung cancer.
Connective tissue-activating peptide III (CTAP III)/ neutrophil activating protein-2 (NAP-2) and haptoglobin were identified to be significantly higher in venous than in arterial blood. CTAP III/NAP-2 levels decreased after tumor resection (P = .01). In two independent population cohorts, CTAP III/NAP-2 was significantly associated with lung cancer and improved the accuracy of a lung cancer risk prediction model that included age, smoking, lung function (FEV1), and an interaction term between FEV1 and CTAP III/NAP-2 (area under the curve, 0.84; 95% CI, 0.77 to 0.91) compared to CAPIII/NAP-2 alone.
We identified CTAP III/NAP-2 as a novel biomarker to detect preclinical lung cancer. The study underscores the importance of applying blood biomarkers as part of a multimodal lung cancer risk prediction model instead of as stand-alone tests.
PMCID: PMC2698017  PMID: 19414677
20.  The effects of long-acting bronchodilators on total mortality in patients with stable chronic obstructive pulmonary disease 
Respiratory Research  2010;11(1):56.
Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of mortality worldwide. Long-acting bronchodilators are considered first line therapies for patients with COPD but their effects on mortality are not well known. We performed a comprehensive systematic review and meta-analysis to evaluate the effects of long-acting bronchodilators on total mortality in stable COPD.
Using MEDLINE, EMBASE and Cochrane Systematic Review databases, we identified high quality randomized controlled trials of tiotropium, formoterol, salmeterol, formoterol/budesonide or salmeterol/fluticasone in COPD that had a follow-up of 6 months or longer and reported on total mortality. Two reviewers independently abstracted data from the original trials and disagreements were resolved by iteration and consensus.
Twenty-seven trials that included 30,495 patients were included in the review. Relative risk (RR) for total mortality was calculated for each of the study and pooled together using a random-effects model. The combination of inhaled corticosteroid (ICS) and long-acting beta-2 agonist (LABA) therapy was associated with reduced total mortality compared with placebo (RR, 0.80; p = 0.005). Neither tiotropium (RR, 1.08; p = 0.61) nor LABA by itself (RR, 0.90; p = 0.21) was associated with mortality.
A combination of ICS and LABA reduced mortality by approximately 20%. Neither tiotropium nor LABA by itself modifies all-cause mortality in COPD.
PMCID: PMC2876086  PMID: 20459831
21.  Associations of IL6 polymorphisms with lung function decline and COPD 
Thorax  2009;64(8):698-704.
Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which likely plays an important role in the pathogenesis of COPD. There is a functional single nucleotide polymorphism (SNP), −174G/C, in the promoter region of IL6. We hypothesized that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers.
Seven and 5 SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in one second (FEV1) over 5 years and baseline FEV1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of 9 IL6 SNPs was genotyped in 389 COPD cases from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS).
In the LHS, three IL6 SNPs were associated with FEV1 decline (0.023 ≤ P ≤ 0.041 in additive models). Among them the IL6_−174C allele was associated with rapid decline of lung function. The association was more significant in a genotype-based analysis (P = 0.006). In the NETT-NAS study, IL6_−174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_−174G/C, were associated with susceptibility to COPD (0.01 ≤ P ≤ 0.04 in additive genetic models).
Our results suggest that the IL6_−174G/C SNP is associated with rapid decline of FEV1 and susceptibility to COPD in smokers.
PMCID: PMC2859187  PMID: 19359268
genetic polymorphism; IL6; forced expiratory volume in one second (FEV1); lung function; chronic obstructive pulmonary disease (COPD)
22.  Integrative Approach to Quality Assessment of Medical Journals Using Impact Factor, Eigenfactor, and Article Influence Scores 
PLoS ONE  2010;5(4):e10204.
Impact factor (IF) is a commonly used surrogate for assessing the scientific quality of journals and articles. There is growing discontent in the medical community with the use of this quality assessment tool because of its many inherent limitations. To help address such concerns, Eigenfactor (ES) and Article Influence scores (AIS) have been devised to assess scientific impact of journals. The principal aim was to compare the temporal trends in IF, ES, and AIS on the rank order of leading medical journals over time.
The 2001 to 2008 IF, ES, AIS, and number of citable items (CI) of 35 leading medical journals were collected from the Institute of Scientific Information (ISI) and the databases. The journals were ranked based on the published 2008 ES, AIS, and IF scores. Temporal score trends and variations were analyzed.
In general, the AIS and IF values provided similar rank orders. Using ES values resulted in large changes in the rank orders with higher ranking being assigned to journals that publish a large volume of articles. Since 2001, the IF and AIS of most journals increased significantly; however the ES increased in only 51% of the journals in the analysis. Conversely, 26% of journals experienced a downward trend in their ES, while the rest experienced no significant changes (23%). This discordance between temporal trends in IF and ES was largely driven by temporal changes in the number of CI published by the journals.
The rank order of medical journals changes depending on whether IF, AIS or ES is used. All of these metrics are sensitive to the number of citable items published by journals. Consumers should thus consider all of these metrics rather than just IF alone in assessing the influence and importance of medical journals in their respective disciplines.
PMCID: PMC2855371  PMID: 20419115
23.  Potential role of stem cells in management of COPD 
Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic affecting over 200 million people and accounting for more than three million deaths annually. The disease is characterized by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking. Unfortunately, there are no interventions that have been unequivocally shown to prolong survival in patients with COPD. Regeneration of lung tissue by stem cells from endogenous and exogenous sources is a promising therapeutic strategy. Herein we review the current literature on the characterization of resident stem and progenitor cell niches within the lung, the contribution of mesenchymal stem cells to lung regeneration, and advances in bioengineering of lung tissue.
PMCID: PMC2865028  PMID: 20463889
COPD; stem cell therapy; epithelial repair; regenerative medicine
24.  Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis 
Respiratory Research  2010;11(1):12.
Previous meta-analyses of treatments for pulmonary arterial hypertension (PAH) have not shown mortality benefit from any individual class of medication.
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through November 2009 for randomized trials that evaluated any pharmacotherapy in the treatment of PAH. Reference lists from included articles and recent review articles were also searched. Analysis included randomized placebo controlled trials of at least eight weeks duration and studies comparing intravenous medication to an unblinded control group.
1541 unique studies were identified and twenty-four articles with 3758 patients were included in the meta-analysis. Studies were reviewed and data extracted regarding study characteristics and outcomes. Data was pooled for three classes of medication: prostanoids, endothelin-receptor antagonists (ERAs), and phosphodiesterase type 5 (PDE5) inhibitors. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated for mortality, 6-minute walk distance, dyspnea scores, hemodynamic parameters, and adverse effects. Mortality in the control arms was a combined 4.2% over the mean study length of 14.9 weeks. There was significant mortality benefit with prostanoid treatment (RR 0.49, CI 0.29 to 0.82), particularly comparing intravenous agents to control (RR 0.30, CI 0.14 to 0.63). Mortality benefit was not observed for ERAs (RR 0.58, CI 0.21 to 1.60) or PDE5 inhibitors (RR 0.30, CI 0.08 to 1.08). All three classes of medication improved other clinical and hemodynamic endpoints. Adverse effects that were increased in treatment arms include jaw pain, diarrhea, peripheral edema, headache, and nausea in prostanoids; and visual disturbance, dyspepsia, flushing, headache, and limb pain in PDE5 inhibitors. No adverse events were significantly associated with ERA treatment.
Treatment of PAH with prostanoids reduces mortality and improves multiple other clinical and hemodynamic outcomes. ERAs and PDE5 inhibitors improve clinical and hemodynamic outcomes, but have no proven effect on mortality. The long-term effects of all PAH treatment requires further study.
PMCID: PMC2835653  PMID: 20113497
25.  Serum Surfactant Protein D during Acute Exacerbations of Chronic Obstructive Pulmonary Disease 
Disease markers  2010;27(6):287-294.
Background: There is a paucity of lung specific biomarkers to diagnose exacerbations of chronic obstructive pulmonary disease (COPD) and to track their progression. Surfactant protein D (SP-D) is a pulmonary collectin regulating the innate immunity of the lung and its serum expression is perturbed in COPD. However, it is not known whether serum levels change during exacerbations. We sought to determine whether serum SP-D levels are raised in COPD exacerbations.
Objectives: To determine whether or not patients with exacerbations have elevated serum SP-D levels compared with asymptomatic controls, stable disease.
Study design: case control study.
Methods: We measured serum SP-D levels from patients with stable COPD (n = 14), patients experiencing acute exacerbations (n = 13) and in control subjects (n = 54) using a specific immunoassay and compared the levels using analysis of variance.
Results: Serum SP-D levels were significantly increased in patients who experienced an acute exacerbation (227 ± 120 ng/mL) compared to patients with stable disease (151 ± 83 ng/mL) or control subjects (128 ± 65 ng/mL; p = 0.003). Serum SP-D levels were also found to be inversely related to various lung function parameters including FEV1/FVC% predicted.
Conclusions: Our study suggests that serum SP-D levels are increased in patients during exacerbations and may be a potential diagnostic biomarker for COPD exacerbations.
PMCID: PMC3834666  PMID: 20075511
Surfactant protein D; serum biomarker; COPD; exacerbations; diagnostic

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