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1.  Optimal Threshold in CT Quantification of Emphysema 
European radiology  2012;23(4):975-984.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00330-012-2683-z
PMCID: PMC3573224  PMID: 23111815
Chronic obstructive pulmonary disease; computed tomography; pulmonary emphysema; density mask; lobe segmentation
2.  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.
doi:10.1038/ni.2565
PMCID: PMC3631463  PMID: 23542741
3.  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.
Results
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).
Conclusions
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.
doi:10.1016/j.acra.2012.06.007
PMCID: PMC3646411  PMID: 22884402
Airway tree architecture; chronic obstructive pulmonary disease; computed tomography; pulmonary function; lung diseases
4.  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 www.clinicaltrials.gov (NCT 00608764).
doi:10.1164/rccm.201109-1618OC
PMCID: PMC3326424  PMID: 22268134
six-minute walk distance; emphysema; interstitial lung disease; subclinical; idiopathic pulmonary fibrosis
5.  Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era 
AIDS (London, England)  2012;26(6):731-740.
Objective
To determine relationship of echocardiographic measures of pulmonary hypertension to lung function and inflammatory biomarkers in HIV-infected individuals.
Design
Cross-sectional study of 116 HIV-infected outpatients.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/QAD.0b013e32835099ae
PMCID: PMC3606053  PMID: 22210636
HIV; pulmonary hypertension; emphysema; COPD; inflammation
6.  Asthma Diagnosis and Airway Bronchodilator Response in HIV-infected Individuals 
Background
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).
Objective
To determine the prevalence of asthma diagnosis and related pulmonary function abnormalities in an HIV-infected cohort and to identify potential mechanisms.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.jaci.2011.11.015
PMCID: PMC3294124  PMID: 22177327
HIV; asthma; airway obstruction; allergy
7.  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.
doi:10.1164/rccm.201106-1094OC
PMCID: PMC3297087  PMID: 22016446
COPD; positive-pressure ventilation; artificial respiration; epidemiology
8.  LUNG DEFLATION AND OXYGEN PULSE IN COPD: RESULTS FROM THE NETT RANDOMIZED TRIAL 
Respiratory medicine  2011;106(1):109-119.
Background
In COPD patients, hyperinflation impairs cardiac function. We examined whether lung deflation improves oxygen pulse, a surrogate marker of stroke volume.
Methods
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.
Results
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).
Conclusion
In COPD, decreased hyperinflation through lung volume reduction is associated with improved O2 pulse.
doi:10.1016/j.rmed.2011.07.012
PMCID: PMC3233645  PMID: 21843930
cardiac function; hyperinflation; lung volume reduction surgery; oxygen pulse
9.  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.
doi:10.1016/j.diagmicrobio.2011.05.008
PMCID: PMC3159032  PMID: 21851870
chronic obstructive pulmonary disease; Pneumocystis jirovecii; lung
10.  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.
doi:10.1080/15412550701246658
PMCID: PMC3391963  PMID: 17530503
Energy Expenditure; COPD; Ambulatory Monitoring; Exercise Test; Activities Of Daily Living
11.  QUANTITATIVE CT ANALYSIS, AIRFLOW OBSTRUCTION AND LUNG CANCER IN THE PITTSBURGH LUNG SCREENING STUDY 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/JTO.0b013e318219aa93
PMCID: PMC3157578  PMID: 21610523
12.  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.
doi:10.1164/rccm.201004-0666OC
PMCID: PMC3086755  PMID: 20935108
pulmonary disease, chronic obstructive; emphysema; osteoporosis
13.  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.
doi:10.1109/TMI.2010.2076300
PMCID: PMC3271357  PMID: 20851792
airway tree segmentation; differential geometry; computer-aided detection; lung CT
14.  Elevated N-Terminal Pro-Brain Natriuretic Peptide Is Associated with Mortality in Tobacco Smokers Independent of Airflow Obstruction 
PLoS ONE  2011;6(11):e27416.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1371/journal.pone.0027416
PMCID: PMC3210169  PMID: 22087311
15.  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.
doi:10.1164/rccm.201001-0043OC
PMCID: PMC2970864  PMID: 20538961
perfusion; computed tomography; emphysema; mortality; lung volume reduction surgery
16.  Pulmonary Function Abnormalities in HIV-Infected Patients during the Current Antiretroviral Therapy Era 
Rationale: Before the introduction of combination antiretroviral (ARV) therapy, patients infected with HIV had an increased prevalence of respiratory symptoms and lung function abnormalities. The prevalence and exact phenotype of pulmonary abnormalities in the current era are unknown. In addition, these abnormalities may be underdiagnosed.
Objectives: Our objective was to determine the current burden of respiratory symptoms, pulmonary function abnormalities, and associated risk factors in individuals infected with HIV.
Methods: Cross-sectional analysis of 167 participants infected with HIV who underwent pulmonary function testing.
Measurements and Main Results: Respiratory symptoms were present in 47.3% of participants and associated with intravenous drug use (odds ratio [OR] 3.64; 95% confidence interval [CI], 1.32–10.046; P = 0.01). Only 15% had previous pulmonary testing. Pulmonary function abnormalities were common with 64.1% of participants having diffusion impairment and 21% having irreversible airway obstruction. Diffusion impairment was independently associated with ever smoking (OR 2.46; 95% CI, 1.16–5.21; P = 0.02) and Pneumocystis pneumonia prophylaxis (OR 2.94; 95% CI, 1.10–7.86; P = 0.01), whereas irreversible airway obstruction was independently associated with pack-years smoked (OR 1.03 per pack-year; 95% CI, 1.01–1.05; P < 0.01), intravenous drug use (OR 2.87; 95% CI, 1.15–7.09; P = 0.02), and the use of ARV therapy (OR 6.22; 95% CI, 1.19–32.43; P = 0.03).
Conclusions: Respiratory symptoms and pulmonary function abnormalities remain common in individuals infected with HIV. Smoking and intravenous drug use are still important risk factors for pulmonary abnormalities, but ARV may be a novel risk factor for irreversible airway obstruction. Obstructive lung disease is likely underdiagnosed in this population.
doi:10.1164/rccm.200912-1858OC
PMCID: PMC2949404  PMID: 20522793
HIV; respiratory function tests; smoking; antiretroviral therapy, highly active; AIDS
17.  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.
doi:10.1164/rccm.201203-0506OC
PMCID: PMC3678112  PMID: 23262513
B cells; T cells; adaptive immunity; interstitial lung disease
18.  Persistent Pneumocystis colonization leads to the development of chronic obstructive pulmonary disease (COPD) in a non-human primate model of AIDS 
The Journal of infectious diseases  2010;202(2):302-312.
HIV-infected patients are at increased risk for development of pulmonary complications, including chronic obstructive pulmonary disease (COPD). Inflammation associated with sub-clinical infection has been postulated to promote COPD. Persistence of Pneumocystis (Pc) is associated with HIV and COPD, although a causal relationship has not been established. We used a simian/human immunodeficiency virus (SHIV) model of HIV infection to study pulmonary effects of Pc colonization. SHIV-infected/Pc-colonized monkeys developed progressive obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Elevated Th2 cytokines and pro-inflammatory mediators in bronchoalveolar lavage fluid coincided with Pc colonization and pulmonary function decline. These results support the concept that an infectious agent contributes to development of HIV-associated lung disease and suggests that Pc colonization may be a risk factor for the development of HIV-associated COPD. Furthermore, this model allows examination of early host responses important to disease progression thus identifying potential therapeutic targets for COPD.
doi:10.1086/653485
PMCID: PMC2946196  PMID: 20533880
Pneumocystis; COPD; SHIV; AIDS; HIV
19.  Oxygen Consumption, Shuttle Walking Test and the Evaluation of Lung Resection 
Respiration  2009;80(1):19-23.
Background
Assessment of peak oxygen uptake (VO2) is recommended in the evaluation of patients with borderline pulmonary function as VO2 is the strongest independent predictor of postoperative pulmonary complications. However, the measurement of VO2 requires expensive equipment not available in many medical facilities. The shuttle walking test (SWT) has been proposed to be used as a screening tool prior to performing a cardiopulmonary exercise test. Although an association exists between SWT distance and VO2, only one small study directly measured VO2 during the SWT.
Objectives
The aim of this study was to further validate the VO2-SWT association by directly measuring VO2 during SWT in a larger cohort of patients with stable chronic obstructive pulmonary disease (COPD).
Methods
Fifty stable COPD patients with mild/severe disease were studied. Each patient performed an SWT while wearing a validated portable metabolic monitor.
Results
Mean VO2 (ml/kg/min) measured after each finalized minute of the SWT was (95% confidence interval): 6 (5–7), 9 (8–10), 11 (10–12), 13 (11–14), 15 (14–16), 18 (16–20) and 21 (18–26) for minutes 1–7, respectively. Patients that completed the British Thoracic Society-recommended 25 shuttles (5 min or 250 m) in the SWT had a mean VO2 of 15 (14–16). The positive predictive value for walking 25 shuttles (predicting a VO2 of ≥15ml/kg/min) was 90% and the negative predictive value was 90%.
Conclusions
Our findings validate the association between VO2 and SWT distance and facilitate the interpretation of the test in general practice, particularly when deciding the candidacy of a patient for surgical resection.
doi:10.1159/000235543
PMCID: PMC2889265  PMID: 19672050
Activities of daily living; Chronic obstructive pulmonary disease; Emphysema; Exercise test; Lung cancer resection; Shuttle walking test
20.  Physiological and Computed Tomographic Predictors of Outcome from Lung Volume Reduction Surgery 
Rationale: Previous investigations have identified several potential predictors of outcomes from lung volume reduction surgery (LVRS). A concern regarding these studies has been their small sample size, which may limit generalizability. We therefore sought to examine radiographic and physiologic predictors of surgical outcomes in a large, multicenter clinical investigation, the National Emphysema Treatment Trial.
Objectives: To identify objective radiographic and physiological indices of lung disease that have prognostic value in subjects with chronic obstructive pulmonary disease being evaluated for LVRS.
Methods: A subset of the subjects undergoing LVRS in the National Emphysema Treatment Trial underwent preoperative high-resolution computed tomographic (CT) scanning of the chest and measures of static lung recoil at total lung capacity (SRtlc) and inspiratory resistance (Ri). The relationship between CT measures of emphysema, the ratio of upper to lower zone emphysema, CT measures of airway disease, SRtlc, Ri, the ratio of residual volume to total lung capacity (RV/TLC), and both 6-month postoperative changes in FEV1 and maximal exercise capacity were assessed.
Measurements and Main Results: Physiological measures of lung elastic recoil and inspiratory resistance were not correlated with improvement in either the FEV1 (R = −0.03, P = 0.78 and R = –0.17, P = 0.16, respectively) or maximal exercise capacity (R = –0.02, P = 0.83 and R = 0.08, P = 0.53, respectively). The RV/TLC ratio and CT measures of emphysema and its upper to lower zone ratio were only weakly predictive of postoperative changes in both the FEV1 (R = 0.11, P = 0.01; R = 0.2, P < 0.0001; and R = 0.23, P < 0.0001, respectively) and maximal exercise capacity (R = 0.17, P = 0.0001; R = 0.15, P = 0.002; and R = 0.15, P = 0.002, respectively). CT assessments of airway disease were not predictive of change in FEV1 or exercise capacity in this cohort.
Conclusions: The RV/TLC ratio and CT measures of emphysema and its distribution are weak but statistically significant predictors of outcome after LVRS.
doi:10.1164/rccm.200906-0911OC
PMCID: PMC2830400  PMID: 19965810
21.  Tacrolimus in refractory polymyositis with interstitial lung disease 
Lancet  1999;353(9166):1762-1763.
doi:10.1016/S0140-6736(99)01927-3
PMCID: PMC2977932  PMID: 10347992
22.  Integrating Health Status and Survival Data 
Rationale: In studies that address health-related quality of life (QoL) and survival, subjects who die are usually censored from QoL assessments. This practice tends to inflate the apparent benefits of interventions with a high risk of mortality. Assessing a composite QoL-death outcome is a potential solution to this problem.
Objectives: To determine the effect of lung volume reduction surgery (LVRS) on a composite endpoint consisting of the occurrence of death or a clinically meaningful decline in QoL defined as an increase of at least eight points in the St. George's Respiratory Questionnaire total score from the National Emphysema Treatment Trial.
Methods: In patients with chronic obstructive pulmonary disease and emphysema randomized to receive medical treatment (n = 610) or LVRS (n = 608), we analyzed the survival to the composite endpoint, the hazard functions and constructed prediction models of the slope of QoL decline.
Measurements and Main Results: The time to the composite endpoint was longer in the LVRS group (2 years) than the medical treatment group (1 year) (P < 0.0001). It was even longer in the subsets of patients undergoing LVRS without a high risk for perioperative death and with upper-lobe-predominant emphysema. The hazard for the composite event significantly favored the LVRS group, although it was most significant in patients with predominantly upper-lobe emphysema. The beneficial impact of LVRS on QoL decline was most significant during the 2 years after LVRS.
Conclusions: LVRS has a significant effect on the composite QoL-survival endpoint tested, indicating its meaningful palliative role, particularly in patients with upper-lobe–predominant emphysema.
doi:10.1164/rccm.200809-1383OC
PMCID: PMC2724716  PMID: 19483114
chronic obstructive pulmonary disease; outcome assessment; palliative care; quality of life; survival; emphysema
23.  Airway Obstruction Is Increased in Pneumocystis-Colonized Human Immunodeficiency Virus-Infected Outpatients▿  
Journal of Clinical Microbiology  2009;47(11):3773-3776.
We investigated the relationship of Pneumocystis colonization, matrix metalloprotease levels in sputum, and airway obstruction in a cohort of human immunodeficiency virus (HIV)-infected outpatients. Pneumocystis-colonized subjects had worse obstruction of airways and higher levels of matrix metalloprotease-12 in sputa, suggesting that Pneumocystis colonization may be important in HIV-associated chronic obstructive pulmonary disease.
doi:10.1128/JCM.01712-09
PMCID: PMC2772636  PMID: 19759224
24.  Comorbidities, Patient Knowledge, and Disease Management in a National Sample of Patients with Chronic Obstructive Pulmonary Disease 
The American journal of medicine  2009;122(4):348-355.
Purpose
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States but is often under-treated. COPD often overlaps with other conditions such as hypertension and osteoporosis, which are less morbid but which may be treated more aggressively. We evaluated the prevalence of these comorbid conditions and compared testing, patient knowledge, and management in a national sample of patients with COPD.
Methods and Methods
A survey was administered by telephone in 2006 to 1,003 COPD patients to evaluate the prevalence of comorbid conditions, diagnostic testing, knowledge, and management using standardized instruments. The completion rate was 87%.
Results
Among 1,003 patients with COPD, 61% reported moderate or severe dyspnea and 41% a prior hospitalization for COPD. The most prevalent comorbid diagnoses were hypertension (55%), hypercholesterolemia (52%), depression (37%), cataracts (31%) and osteoporosis (28%). Only 10% of respondents knew their FEV1 (95% CI: 8, 12%) compared to 79% who knew their blood pressure (95% CI: 76%, 83%). Seventy-two percent (95% CI: 69%, 75%) reported taking any medication for COPD – usually a short-acting bronchodilator – whereas 87% (95% CI: 84%, 90%) of patients with COPD and hypertension were taking an antihypertensive medication and 72% (95% CI: 68%, 75%) of patients with COPD and hypercholesterolemia were taking a statin.
Conclusion
Although most of these COPD patients in this national sample were symptomatic and many had been hospitalized for COPD, COPD self-knowledge was low and COPD was undertreated compared to generally asymptomatic, less morbid conditions such as hypertension.
doi:10.1016/j.amjmed.2008.09.042
PMCID: PMC2692705  PMID: 19332230
chronic obstructive pulmonary disease; emphysema; chronic bronchitis; asthma; comorbidities
25.  A Computational Geometry Approach to Automated Pulmonary Fissure Segmentation in CT Examinations 
Identification of pulmonary fissures, which form the boundaries between the lobes in the lungs, may be useful during clinical interpretation of CT examinations to assess the early presence and characterization of manifestation of several lung diseases. Motivated by the unique nature of the surface shape of pulmonary fissures in three-dimensional space, we developed a new automated scheme using computational geometry methods to detect and segment fissures depicted on CT images. After a geometric modeling of the lung volume using the Marching Cube Algorithm, Laplacian smoothing is applied iteratively to enhance pulmonary fissures by depressing non-fissure structures while smoothing the surfaces of lung fissures. Next, an Extended Gaussian Image based procedure is used to locate the fissures in a statistical manner that approximates the fissures using a set of plane “patches.” This approach has several advantages such as independence of anatomic knowledge of the lung structure except the surface shape of fissures, limited sensitivity to other lung structures, and ease of implementation. The scheme performance was evaluated by two experienced thoracic radiologists using a set of 100 images (slices) randomly selected from 10 screening CT examinations. In this preliminary evaluation 98.7% and 94.9% of scheme segmented fissure voxels are within 2 mm of the fissures marked independently by two radiologists in the testing image dataset. Using the scheme detected fissures as reference, 89.4% and 90.1% of manually marked fissure points have distance ≤ 2 mm to the reference suggesting a possible under-segmentation of the scheme. The case-based RMS (root-mean-square) distances (“errors”) between our scheme and the radiologist ranged from 1.48±0.92 to 2.04±3.88 mm. The discrepancy of fissure detection results between the automated scheme and either radiologist is smaller in this dataset than the inter-reader variability.
doi:10.1109/TMI.2008.2010441
PMCID: PMC2839918  PMID: 19272987
Pulmonary fissure; Segmentation; Computer-aided detection; Shape analysis; Extended Gaussian Image (EGI)

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