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1.  Plasma inflammatory mediators associated with bone metabolism in COPD 
COPD  2010;7(3):186-191.
The association of osteoporosis with COPD is well established, but the relationship between systemic inflammatory mediators and bone metabolism has not been explored.
Materials and Methods
Plasma samples from 40 COPD patients awaiting lung transplantation were analyzed for 27 inflammatory mediators using a multiplex protein array. C-telopeptide type I collagen (CTx), a marker of bone resorption, was measured with ELISA, and N-terminal procollagen propeptide (P1NP), a marker of bone formation, was ascertained with a radioimmunoassay. Associations between inflammatory mediators versus CTx and P1NP with adjustments for steroid and bisphosphonate use were determined.
Mean age was 59 years (± 6) and FEV1 was 23.5% (± 8.3%) predicted. Ninety-five percent of the subjects had low bone mineral density measured by dual x-ray absorptiometry (DXA). Tumor necrosis factor alpha and interleukin 4 were positively associated with CTx and P1NP. RANTES and eotaxin were inversely associated with CTx and P1NP. Interleukin 2 and interferon gamma were also directly associated with P1NP.
Biologically plausible systemic mediators are associated with bone metabolism in patients with severe COPD, offering potential insight into risk factors and underlying mechanisms of bone disease. Furthermore, they may be useful in monitoring disease activity, and serve as targets for biological therapy.
PMCID: PMC3985167  PMID: 20486817
Pulmonary disease; chronic obstructive; Osteoporosis; Inflammation; Cytokines
2.  Assessment of Lung Volume Collapsibility in Chronic Obstructive Lung Disease Patients Using CT 
European radiology  2013;23(6):1564-1572.
To investigate the collapsibility of the lung and individual lobes in patients with COPD during inspiration/expiration and assess the association of whole lung and lobar volume changes with pulmonary function tests (PFTs) and disease severity.
PFT measures used were RV/TLC%, FEV1% predicted, FVC, FEV1/FVC%, DLco% predicted and GOLD category. A total of 360 paired inspiratory and expiratory CT examinations acquired in 180 subjects were analysed. Automated computerised algorithms were used to compute individual lobe and total lung volumes. Lung volume collapsibility was assessed quantitatively using the simple difference between CT computed inspiration (I) and expiration (E) volumes (I-E), and a relative measure of volume changes, (I-E)/I.
Mean absolute collapsibility (I-E) decreased in all lung lobes with increasing disease severity defined by GOLD classification. Relative collapsibility (I-E)/I showed a similar trend. Upper lobes had lower volume collapsibility across all GOLD categories and lower lobes collectively had the largest volume collapsibility. Whole lung and left lower lobe collapsibility measures tended to have the highest correlations with PFT measures. Collapsibility of lung lobes and whole lung were also negatively correlated with the degree of air trapping between expiration and inspiration, as measured by mean lung density. All measured associations were statistically significant (P < 0.01).
Severity of COPD appears associated with increased collapsibility in the upper lobes, but change (decline) in collapsibility is faster in the lower lobes.
PMCID: PMC3657332  PMID: 23494492
lung volume; collapsibility; COPD; computed tomography; disease severity
3.  Pulmonary Fissure Integrity and Collateral Ventilation in COPD Patients 
PLoS ONE  2014;9(5):e96631.
To investigate whether the integrity (completeness) of pulmonary fissures affects pulmonary function in patients with chronic obstructive pulmonary disease (COPD).
Materials and Methods
A dataset consisting of 573 CT exams acquired on different subjects was collected from a COPD study. According to the global initiative for chronic obstructive lung disease (GOLD) criteria, these subjects (examinations) were classified into five different subgroups, namely non-COPD (222 subjects), GOLD-I (83 subjects), GOLD-II (141 subjects), GOLD-III (63 subjects), and GOLD-IV (64 subjects), in terms of disease severity. An available computer tool was used to aid in an objective and efficient quantification of fissure integrity. The correlations between fissure integrity, and pulmonary functions (e.g., FEV1, and FEV1/FVC) and COPD severity were assessed using Pearson and Spearman's correlation coefficients, respectively.
For the five sub-groups ranging from non-COPD to GOLD-IV, the average integrities of the right oblique fissure (ROF) were 81.8%, 82.4%, 81.8%, 82.8%, and 80.2%, respectively; the average integrities of the right horizontal fissure (RHF) were 62.6%, 61.8%, 62.1%, 62.2%, and 62.3%, respectively; the average integrities of the left oblique fissure (LOF) were 82.0%, 83.2%, 81.7%, 82.0%, and 78.4%, respectively; and the average integrities of all fissures in the entire lung were 78.0%, 78.6%, 78.1%, 78.5%, and 76.4%, respectively. Their Pearson correlation coefficients with FEV1 and FE1/FVC range from 0.027 to 0.248 with p values larger than 0.05. Their Spearman correlation coefficients with COPD severity except GOLD-IV range from −0.013 to −0.073 with p values larger than 0.08.
There is no significant difference in fissure integrity for patients with different levels of disease severity, suggesting that the development of COPD does not change the completeness of pulmonary fissures and incomplete fissures alone may not contribute to the collateral ventilation.
PMCID: PMC4011857  PMID: 24800803
4.  Optimal Threshold in CT Quantification of Emphysema 
European radiology  2012;23(4):975-984.
To determine the optimal threshold by quantitatively assessing the extent of emphysema at the level of the entire lung and at the level of individual lobes using a large, diverse dataset of CT examinations.
This study comprises 573 chest CT examinations acquired from different subjects (222 none, 83 mild, 141 moderate, 63 severe, and 64 very severe obstruction). The extent of emphysema was quantified using the percentage of the low attenuation area (LAA%) divided by the total lung or lobe volume(s). The correlations between the extent of emphysema, and pulmonary functions and the five-category classification were assessed using Pearson and Spearman’s correlation coefficients, respectively. When quantifying emphysema using a density mask, a wide range of thresholds from −850 to −1000 HU were used.
The highest correlations of LAA% with the five-category classification and PFT measures ranged from −925 to −965 HU for each individual lobe and the entire lung. However, the differences between the highest r and those obtained at −950 HU are relatively small.
Although there are variations in the optimal cut-off thresholds for individual lobes, the single threshold of −950 HU is still an acceptable threshold for density-based emphysema quantification.
PMCID: PMC3573224  PMID: 23111815
Chronic obstructive pulmonary disease; computed tomography; pulmonary emphysema; density mask; lobe segmentation
5.  Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses 
Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations.
Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF.
Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti–heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies.
Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0–8.6; P < 0.0001). HSP70 protein, antigen–antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression.
Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.
PMCID: PMC3678112  PMID: 23262513
B cells; T cells; adaptive immunity; interstitial lung disease
6.  A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation 
Nature immunology  2013;14(5):470-479.
Uncontrolled activation of tumor necrosis factor receptor-associated factor (TRAF) proteins may result in profound tissue injury by linking surface signals to cytokine release. Here we show that a ubiquitin E3 ligase component, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2. Fbxo3 and TRAF protein in circulation positively correlated with cytokine responses in septic subjects and we furthermore identified a hypofunctional Fbxo3 human polymorphism. A small molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several murine disease models. These studies identify a pathway of innate immunity that may characterize subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.
PMCID: PMC3631463  PMID: 23542741
7.  Three-dimensional Airway Tree Architecture and Pulmonary Function 
Academic radiology  2012;19(11):1395-1401.
Rationale and Objectives
The airway tree is a primary conductive structure, and airways’ morphologic characteristics, or variations thereof, may have an impact on airflow, thereby affecting pulmonary function. The objective of this study was to investigate the correlation between airway tree architecture, as depicted on computed tomography, and pulmonary function.
Materials and Methods
A total of 548 chest computed tomographic examinations acquired on different patients at full inspiration were included in this study. The patients were enrolled in a study of chronic obstructive pulmonary disease (Specialized Center for Clinically Oriented Research) and underwent pulmonary function testing in addition to computed tomographic examinations. A fully automated airway tree segmentation algorithm was used to extract the three-dimensional airway tree from each examination. Using a skeletonization algorithm, airway tree volume–normalized architectural measures, including total airway length, branch count, and trachea length, were computed. Correlations between airway tree measurements with pulmonary function testing parameters and chronic obstructive pulmonary disease severity in terms of the Global Initiative for Obstructive Lung Disease classification were computed using Spearman’s rank correlations.
Non-normalized total airway volume and trachea length were associated (P < .01) with lung capacity measures (ie, functional residual capacity, total lung capacity, inspiratory capacity, vital capacity, residual volume, and forced expiratory vital capacity). Spearman’s correlation coefficients ranged from 0.27 to 0.55 (P < .01). With the exception of trachea length, all normalized architecture-based measures (ie, total airway volume, total airway length, and total branch count) had statistically significant associations with the lung function measures (forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced expiratory vital capacity), and adjusted volume was associated with all three respiratory impedance measures (lung reactance at 5 Hz, lung resistance at 5 Hz, and lung resistance at 20 Hz), and adjusted branch count was associated with all respiratory impedance measures but lung resistance at 20 Hz. When normalized for lung volume, all airway architectural measures were statistically significantly associated with chronic obstructive pulmonary disease severity, with Spearman’s correlation coefficients ranging from −0.338 to −0.546 (P < .01).
Despite the large variability in anatomic characteristics of the airway tree across subjects, architecture-based measures demonstrated statistically significant associations (P < .01) with nearly all pulmonary function testing measures, as well as with disease severity.
PMCID: PMC3646411  PMID: 22884402
Airway tree architecture; chronic obstructive pulmonary disease; computed tomography; pulmonary function; lung diseases
8.  Randomized Trial of Zileuton for Treatment of COPD Exacerbations Requiring Hospitalization 
COPD  2011;8(1):21-29.
Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations.
We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization.
Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production.
Main Findings
Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75±2.19 vs. 3.86±3.06 days for zileuton vs. placebo, p=0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p=0.63) despite a decline in urinary LTE4 levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine −1.38± 1.19 vs. 0.14±1.51, p<0.0001) and 72 hours (−1.32±2.08 vs. 0.26±1.93, p<0.006). Adverse events were similar in both groups.
Principal Conclusions
While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE4 levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.
PMCID: PMC3775706  PMID: 21299475
Chronic Obstructive Pulmonary Disease (COPD); Acute exacerbation of COPD (AECOPD); Leukotrienes; Zileuton; Clinical trial
9.  Long-term Comparative Immunogenicity of Protein Conjugate and Free Polysaccharide Pneumococcal Vaccines in Chronic Obstructive Pulmonary Disease 
The Food and Drug Adminstration recently approved a diphtheria-conjugated pneumococcal polysaccharide vaccine for adults, although its long-term immunogenicity is unknown. We report that, in patients with moderate to severe chronic obstructive pulmonary disease, conjugate vaccination elicits a superior immune response to free-polysaccharide vaccine that persists for >2 years.
Background. Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years.
Methods. One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years.
Results. Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed.
Conclusions. PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points.
Clinical Trials Registration: NCT00457977.
PMCID: PMC3491850  PMID: 22652582
10.  Radiographic Emphysema Predicts Low Bone Mineral Density in a Tobacco-exposed Cohort 
Rationale: Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied.
Objectives: We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers.
Methods: One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed.
Measurements and Main Results: No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P = 0.0003). Quantitative emphysema, but not CT-measured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio = 2.55; 95% confidence interval, 1.24–5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use.
Conclusions: Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.
PMCID: PMC3086755  PMID: 20935108
pulmonary disease, chronic obstructive; emphysema; osteoporosis
11.  Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD 
Respiratory Research  2013;14(1):42.
Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.
Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema.
In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.
Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.
PMCID: PMC3627637  PMID: 23566024
Emphysema; Chest CT scan; Small airways; Lung function tests; Smoking
12.  Interstitial Lung Abnormalities and Reduced Exercise Capacity 
Rationale: The relationship between interstitial lung abnormalities (ILA) and exercise capacity has not been comprehensively evaluated.
Objectives: To assess the validity of the 6-minute walk test in subjects with ILA, and to examine the association between ILA and 6-minute walk distance (6MWD).
Methods: Spearman correlation coefficients were used to assess the strength of the relationships between 6MWD and relevant measures of dyspnea, health-related quality of life, and pulmonary function in a cohort of 2,416 people who smoke from the COPDGene study. Unadjusted and adjusted linear and logistic regression models were used to assess the strength of the association between ILA and 6MWD.
Measurements and Main Results: In all subjects, and in those with ILA, 6MWD in COPDGene was associated with relevant clinical and physiologic measures. The mean 6MWD in COPDGene subjects with ILA was 386 m (SD, 128 m), and 82% and 19% of subjects with ILA had 6MWDs less than or equal to 500 and 250 m, respectively. ILA was associated with a reduced 6MWD in univariate (−30 m; 95% confidence interval, −50 to −10; P = 0.004) and multivariate models (−19 m; 95% confidence interval, −33 to −5; P = 0.008). Compared with subjects without ILA, subjects with ILA had an 80% and 77% increase in their odds to have a walk distance limited to less than or equal to 500 and 250 m, respectively. Although these findings were dependent on ILA subtype, they were not limited to those with COPD.
Conclusions: Our study demonstrates that ILA is associated with measurable decrements in the 6MWD of people who smoke.
Clinical trial registered with (NCT 00608764).
PMCID: PMC3326424  PMID: 22268134
six-minute walk distance; emphysema; interstitial lung disease; subclinical; idiopathic pulmonary fibrosis
13.  Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era 
AIDS (London, England)  2012;26(6):731-740.
To determine relationship of echocardiographic measures of pulmonary hypertension to lung function and inflammatory biomarkers in HIV-infected individuals.
Cross-sectional study of 116 HIV-infected outpatients.
Doppler-echocardiography and pulmonary function testing were performed. Induced sputum and plasma cytokines, sputum cell counts and differentials, markers of peripheral T cell activation, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Univariate and multivariate analyses determined relationship of echocardiographic variables to pulmonary function, inflammation, and NT-proBNP.
Mean estimated pulmonary artery systolic pressure (PASP) was 34.3 mmHg (SD 6.9) and mean tricuspid regurgitant jet velocity (TRV) was 2.5 m/sec (SD 0.32). Eighteen participants (15.5%) had PASP of at least 40 mmHg, and 9 (7.8%) had TRV of at least 3.0 m/sec. Elevated TRV was significantly associated with CD4 cell counts below 200 cells/μl and higher log HIV RNA levels. Forced expiratory volume in one second (FEV1) percent predicted, FEV1/forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLco) percent predicted were significantly lower in those with elevated PASP or TRV. Sputum interleukin-8, peripheral interleukin-8, peripheral interferon-γ levels, and CD8+ T-cell expression of CD69+ were associated increased with increasing PASP and TRV. Log NT-proBNP was significantly higher with increasing PASP and TRV. Left ventricular function was not associated with PASP or TRV.
Echocardiographic manifestations of pulmonary hypertension are common in HIV and are associated with respiratory symptoms, more advanced HIV disease, airway obstruction, abnormal DLco, and systemic and pulmonary inflammation. Pulmonary hypertension and COPD coexist in HIV and may arise secondary to common inflammatory mechanisms.
PMCID: PMC3606053  PMID: 22210636
HIV; pulmonary hypertension; emphysema; COPD; inflammation
14.  Asthma Diagnosis and Airway Bronchodilator Response in HIV-infected Individuals 
Despite the high prevalence of respiratory symptoms and obstructive lung disease in HIV-infected persons, the prevalence of bronchodilator reversibility (BDR) and asthma has not been systematically studied during the era of combination antiretroviral therapy (ART).
To determine the prevalence of asthma diagnosis and related pulmonary function abnormalities in an HIV-infected cohort and to identify potential mechanisms.
A cross-sectional analysis of 223 HIV-infected individuals with data on respiratory symptoms and diagnoses, pulmonary function, sputum cell counts, and asthma-related cytokines and chemokines in serum/sputum.
Doctor-diagnosed asthma was present in 46 (20.6%) and BDR (≥200ml and ≥12% increase in FEV1 or FVC) in 20 participants (9.0%). Pulmonary symptoms and function were worse in those with doctor-diagnosed asthma. Doctor-diagnosed asthma was independently associated with female sex (p=0.04), body mass index >29.6kg/m2 (vs.<29.6kg/m2) (p=0.03), history of bacterial or Pneumocystis pneumonia (p=0.01), and with not currently taking ART (p=0.04), and in univariate analysis with parental history of asthma (n=180; p=0.004). High sputum eosinophil percentages (>2.3% based on the highest decile) were more likely in those with doctor-diagnosed asthma (p=0.02) or BDR (p=0.02). Doctor-diagnosed asthma tended to be more common with high sputum IL-4 (p=0.02) and RANTES (p=0.02), while BDR was associated with high plasma macrophage inflammatory protein (MIP)-1α (p=0.002), and sputum MIP-1β levels (p=0.001).
Asthma diagnosis and BDR are prevalent in an HIV-infected outpatient cohort, and associations with family history, obesity, allergic inflammation, prior infection, the absence of ART, and elevated HIV-stimulated cytokines suggest possible mechanisms of HIV-associated asthma.
PMCID: PMC3294124  PMID: 22177327
HIV; asthma; airway obstruction; allergy
15.  Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema 
PLoS ONE  2013;8(2):e56352.
Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema.
Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period.
Main Results
Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline.
MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.
PMCID: PMC3575373  PMID: 23441181
16.  Outcomes of Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the United States, 1998–2008 
Rationale: The patterns and outcomes of noninvasive, positive-pressure ventilation (NIPPV) use in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) nationwide are unknown.
Objectives: To determine the prevalence and trends of noninvasive ventilation for acute COPD.
Methods: We used data from the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample to assess the pattern and outcomes of NIPPV use for acute exacerbations of COPD from 1998 to 2008.
Measurements and Main Results: An estimated 7,511,267 admissions for acute exacerbations occurred from 1998 to 2008. There was a 462% increase in NIPPV use (from 1.0 to 4.5% of all admissions) and a 42% decline in invasive mechanical ventilation (IMV) use (from 6.0 to 3.5% of all admissions) during these years. This was accompanied by an increase in the size of a small cohort of patients requiring transition from NIPPV to IMV. In-hospital mortality in this group appeared to be worsening over time. By 2008, these patients had a high mortality rate (29.3%), which represented 61% higher odds of death compared with patients directly placed on IMV (95% confidence interval, 24–109%) and 677% greater odds of death compared with patients treated with NIPPV alone (95% confidence interval, 475–948%). With the exception of patients transitioned from NIPPV to IMV, in-hospital outcomes were favorable and improved steadily year by year.
Conclusions: The use of NIPPV has increased significantly over time among patients hospitalized for acute exacerbations of COPD, whereas the need for intubation and in-hospital mortality has declined. However, the rising mortality rate in a small but expanding group of patients requiring invasive mechanical ventilation after treatment with noninvasive ventilation needs further investigation.
PMCID: PMC3297087  PMID: 22016446
COPD; positive-pressure ventilation; artificial respiration; epidemiology
Respiratory medicine  2011;106(1):109-119.
In COPD patients, hyperinflation impairs cardiac function. We examined whether lung deflation improves oxygen pulse, a surrogate marker of stroke volume.
In 129 NETT patients with cardiopulmonary exercise testing (CPET) and arterial blood gases (ABG substudy), hyperinflation was assessed with residual volume to total lung capacity ratio (RV/TLC), and cardiac function with oxygen pulse (O2 pulse=VO2/HR) at baseline and 6 months. Medical and surgical patients were divided into “deflators” and “non-deflators” based on change in RV/TLC from baseline (ΔRV/TLC). We defined deflation as the ΔRV/TLC experienced by 75% of surgical patients. We examined changes in O2 pulse at peak and similar (iso-work) exercise. Findings were validated in 718 patients who underwent CPET without ABGs.
In the ABG substudy, surgical and medical deflators improved their RV/TLC and peak O2 pulse (median ΔRV/TLC −18.0% vs. −9.3%, p=0.0003; median ΔO2 pulse 13.6% vs. 1.8%, p=0.12). Surgical deflators also improved iso-work O2 pulse (0.53 mL/beat, p=0.04 at 20 watts). In the validation cohort, surgical deflators experienced a greater improvement in peak O2 pulse than medical deflators (mean 18.9% vs. 1.1%). In surgical deflators improvements in O2 pulse at rest and during unloaded pedaling (0.32 mL/beat, p<0.0001 and 0.47 mL/beat, p<0.0001, respectively) corresponded with significant reductions in HR and improvements in VO2. On multivariate analysis, deflators were 88% more likely than non-deflators to have an improvement in O2 pulse (OR 1.88, 95% CI 1.30–2.72, p=0.0008).
In COPD, decreased hyperinflation through lung volume reduction is associated with improved O2 pulse.
PMCID: PMC3233645  PMID: 21843930
cardiac function; hyperinflation; lung volume reduction surgery; oxygen pulse
18.  Distribution of Pneumocystis jirovecii in lungs from colonized COPD patients 
Pneumocystis jirovecii has been detected in lung tissue from patients with chronic obstructive pulmonary disease (COPD) and is associated with disease severity. The regional distribution of the organism in lungs is unknown, but differences in distribution of Pneumocystis could affect estimates of colonization prevalence. We examined the distribution of Pneumocystis in the lungs of 19 non-HIV-infected patients with COPD who were undergoing lung transplantation. DNA was extracted from explanted lungs. We found Pneumocystis colonization in lung tissue of 42.1% of patients with advanced COPD; however, there was significant regional variation in colonization between lung segments of individual patients. Colonization was detected more commonly in the lower and middle lobes than the upper lobes. These findings suggest that single samples from an individual may underestimate the prevalence of Pneumocystis colonization and future studies may obtain a higher yield of Pneumocystis colonization detection when sampling the lower lobes.
PMCID: PMC3159032  PMID: 21851870
chronic obstructive pulmonary disease; Pneumocystis jirovecii; lung
19.  Activity Monitoring and Energy Expenditure in COPD Patients: A Validation Study 
COPD  2007;4(2):107-112.
There is increasing interest in the objective measurement of physical activity in chronic obstructive pulmonary disease (COPD) patients due to the close relationship between physical activity level, health, disability and mortality. We aimed to (a) determine the validity and reproducibility of an activity monitor that integrates accelerometry with multiple physiologic sensors in the determination of energy expenditure in COPD subjects and (b) to document the independent contribution of the additional physiologic sensors to accelerometry measures in improving true energy expenditure determination. Eight subjects (4 male, FEV1 56.4 ± 14.1%, RV 145.0 ± 75.7%) performed 2 separate 6-minute walk and 2 incremental shuttle walk exercise tests. Energy expenditure was calculated during each exercise test using the physiologic activity monitor and compared to a validated exhaled breath metabolic system. Test-retest reproducibility of physiologic activity monitor during the walking tests was comparable to an exhaled breath metabolic system. Physiologic sensor data significantly improved the explained variance in energy expenditure determination (r2= 0.88) compared to accelerometry data alone (r2 = 0.68). This physiologic activity monitor provides a valid and reproducible estimate of energy expenditure during slow to moderate paced walking in a laboratory setting and represents an objective method to assess activity in COPD subjects.
PMCID: PMC3391963  PMID: 17530503
Energy Expenditure; COPD; Ambulatory Monitoring; Exercise Test; Activities Of Daily Living
To study the relationship between emphysema, airflow obstruction and lung cancer in a high risk population we performed quantitative analysis of screening computed tomography (CT) scans.
Subjects completed questionnaires, spirometry and low-dose helical chest CT. Analyses compared cases and controls according to automated quantitative analysis of lung parenchyma and airways measures.
Our case-control study of 117 matched pairs of lung cancer cases and controls did not reveal any airway or lung parenchymal findings on quantitative analysis of screening CT scans that were associated with increased lung cancer risk. Airway measures including wall area %, lumen perimeter, lumen area and average wall HU, and parenchymal measures including lung fraction < −910 Hounsfield Units (HU), were not statistically different between cases and controls.
The relationship between visual assessment of emphysema and increased lung cancer risk could not be verified by quantitative analysis of low-dose screening CT scans in a high risk tobacco exposed population.
PMCID: PMC3157578  PMID: 21610523
22.  Azithromycin for Prevention of Exacerbations of COPD 
The New England journal of medicine  2011;365(8):689-698.
Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.
We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.
A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).
Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; number, NCT00325897.)
PMCID: PMC3220999  PMID: 21864166
23.  A Differential Geometric Approach to Automated Segmentation of Human Airway Tree 
Airway diseases are frequently associated with morphological changes that may affect the physiology of the lungs. Accurate characterization of airways may be useful for quantitatively assessing prognosis and for monitoring therapeutic efficacy. The information gained may also provide insight into the underlying mechanisms of various lung diseases. We developed a computerized scheme to automatically segment the three-dimensional human airway tree depicted on CT images. The method takes advantage of both principal curvatures and principal directions in differentiating airways from other tissues in geometric space. A “puzzle game” procedure is used to identify false negative regions and reduce false positive regions that do not meet the shape analysis criteria. The negative impact of partial volume effects on small airway detection is partially alleviated by repeating the developed differential geometric analysis on lung anatomical structures modeled at multiple iso-values (thresholds). In addition to having advantages, such as full automation, easy implementation and relative insensitivity to image noise and/or artifacts, this scheme has virtually no leakage issues and can be easily extended to the extraction or the segmentation of other tubular type structures (e.g., vascular tree). The performance of this scheme was assessed quantitatively using 75 chest CT examinations acquired on 45 subjects with different slice thicknesses and using 20 publicly available test cases that were originally designed for evaluating the performance of different airway tree segmentation algorithms.
PMCID: PMC3271357  PMID: 20851792
airway tree segmentation; differential geometry; computer-aided detection; lung CT
24.  Elevated N-Terminal Pro-Brain Natriuretic Peptide Is Associated with Mortality in Tobacco Smokers Independent of Airflow Obstruction 
PLoS ONE  2011;6(11):e27416.
Tobacco use is associated with an increased prevalence of cardiovascular disease. N-terminal pro-brain natiuretic peptide (NT-proBNP), a widely available biomarker that is associated with cardiovascular outcomes in other conditions, has not been investigated as a predictor of mortality in tobacco smokers. We hypothesized that NT-proBNP would be an independent prognostic marker in a cohort of well-characterized tobacco smokers without known cardiovascular disease.
Clinical data from 796 subjects enrolled in two prospective tobacco exposed cohorts was assessed to determine factors associated with elevated NT-proBNP and the relationship of these factors and NT-proBNP with mortality.
Subjects were followed for a median of 562 (IQR 252 – 826) days. Characteristics associated with a NT-proBNP above the median (≥49 pg/mL) were increased age, female gender, and decreased body mass index. By time-to-event analysis, an NT-proBNP above the median (≥49 pg/mL) was a significant predictor of mortality (log rank p = 0.02). By proportional hazard analysis controlling for age, gender, cohort, and severity of airflow obstruction, an elevated NT-proBNP level (≥49 pg/mL) remained an independent predictor of mortality (HR = 2.19, 95% CI 1.07–4.46, p = 0.031).
Elevated NT-proBNP is an independent predictor of mortality in tobacco smokers without known cardiovascular disease, conferring a 2.2 fold increased risk of death. Future studies should assess the ability of this biomarker to guide further diagnostic testing and to direct specific cardiovascular risk reduction inventions that may positively impact quality of life and survival.
PMCID: PMC3210169  PMID: 22087311
25.  Perfusion Scintigraphy and Patient Selection for Lung Volume Reduction Surgery 
Rationale: It is unclear if lung perfusion can predict response to lung volume reduction surgery (LVRS).
Objectives: To study the role of perfusion scintigraphy in patient selection for LVRS.
Methods: We performed an intention-to-treat analysis of 1,045 of 1,218 patients enrolled in the National Emphysema Treatment Trial who were non–high risk for LVRS and had complete perfusion scintigraphy results at baseline. The median follow-up was 6.0 years. Patients were classified as having upper or non–upper lobe–predominant emphysema on visual examination of the chest computed tomography and high or low exercise capacity on cardiopulmonary exercise testing at baseline. Low upper zone perfusion was defined as less than 20% of total lung perfusion distributed to the upper third of both lungs as measured on perfusion scintigraphy.
Measurements and Main Results: Among 284 of 1,045 patients with upper lobe–predominant emphysema and low exercise capacity at baseline, the 202 with low upper zone perfusion had lower mortality with LVRS versus medical management (risk ratio [RR], 0.56; P = 0.008) unlike the remaining 82 with high perfusion where mortality was unchanged (RR, 0.97; P = 0.62). Similarly, among 404 of 1,045 patients with upper lobe–predominant emphysema and high exercise capacity, the 278 with low upper zone perfusion had lower mortality with LVRS (RR, 0.70; P = 0.02) unlike the remaining 126 with high perfusion (RR, 1.05; P = 1.00). Among the 357 patients with non–upper lobe–predominant emphysema (75 with low and 282 with high exercise capacity) there was no improvement in survival with LVRS and measurement of upper zone perfusion did not contribute new prognostic information.
Conclusions: Compared with optimal medical management, LVRS reduces mortality in patients with upper lobe–predominant emphysema when there is low rather than high perfusion to the upper lung.
PMCID: PMC2970864  PMID: 20538961
perfusion; computed tomography; emphysema; mortality; lung volume reduction surgery

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