Respiratory Tract Diseases Commons^™

Heme Metabolism Genes Downregulated In Copd Cachexia, Ava C. Wilson, Preeti L. Kumar, Sool Lee, Margaret M. Parker, Itika Arora, Jarrett D. Morrow, Emiel F.M. Wouters, Richard Casaburi, Stephen I. Rennard, David A. Lomas, Alvar Agusti, Ruth Tal-Singer, Mark T. Dransfield, J. Michael Wells, Surya P. Bhatt, George Washko, Victor J. Thannickal, Hemant K. Tiwari, Craig P. Hersh, Peter J. Castaldi, Edwin K. Silverman, Merry-Lynn N. Mcdonald

Journal Articles: Pulmonary & Critical Care Med

INTRODUCTION: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

METHODS: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (<  20 kg/m

RESULTS: The prevalence of …

It's More Than Low Bmi: Prevalence Of Cachexia And Associated Mortality In Copd, Merry-Lynn N. Mcdonald, Emiel F.M. Wouters, Erica Rutten, Richard Casaburi, Stephen I. Rennard, David A. Lomas, Marcas Bamman, Bartolome Celli, Alvar Agusti, Ruth Tal-Singer, Craig P. Hersh, Mark Dransfield, Edwin K. Silverman

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Cachexia is associated with increased mortality risk among chronic obstructive pulmonary disease (COPD) patients. However, low body mass index (BMI) as opposed to cachexia is often used, particularly when calculating the BODE (BMI, Obstruction, Dyspnea and Exercise) index. For this reason, we examined mortality using a consensus definition and a weight-loss definition of cachexia among COPD cases and compared two new COPD severity indices with BODE.

METHODS: In the current report, the consensus definition for cachexia incorporated weight-loss > 5% in 12-months or low BMI in addition to 3/5 of decreased muscle strength, fatigue, anorexia, low FFMI and inflammation. The …

Imaging-Based Clusters In Former Smokers Of The Copd Cohort Associate With Clinical Characteristics: The Subpopulations And Intermediate Outcome Measures In Copd Study (Spiromics), Babak Haghighi, Sanghun Choi, Jiwoong Choi, Eric A. Hoffman, Alejandro P. Comellas, John D. Newell, Chang Hyun Lee, R. Graham Barr, Eugene Bleecker, Christopher B. Cooper, David Couper, Mei Lan Han, Nadia N. Hansel, Richard E. Kanner, Ella A. Kazerooni, Eric A.C. Kleerup, Fernando J. Martinez, Wanda O'Neal, Robert Paine, Stephen I. Rennard, Benjamin M. Smith, Prescott G. Woodruff, Ching-Long Lin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping.

METHODS: An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, …

The Impact Of Pulmonary Hypertension In Preterm Infants With Severe Bronchopulmonary Dysplasia Through 1 Year., Joanne M. Lagatta, Erik B. Hysinger, Isabella Zaniletti, Erica M. Wymore, Shilpa Vyas-Read, Sushmita Yallapragada, Leif D. Nelin, William E. Truog, Michael A. Padula, Nicolas F M Porta, Rashmin C. Savani, Karin P. Potoka, Steven M. Kawut, Robert Digeronimo, Girija Natarajan, Huayan Zhang, Theresa R. Grover, William A. Engle, Karna Murthy, Children's Hospital Neonatal Consortium Severe Bpd Focus Group

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVES: To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia.

STUDY DESIGN: This was a multicenter, retrospective cohort study of 1677 infants bornChildren's Hospital Neonatal Consortium with records linked to the Pediatric Health Information System.

RESULTS: Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10-4.73, P < .001), ventilator support at 36 weeks of postmenstrual age (60% vs 40%, P < .001), duration of ventilation (72 IQR 30-124 vs 41 IQR 17-74 days, P < .001), and higher respiratory severity score (3.6 IQR 0.4-7.0 vs 0.8 IQR 0.3-3.3, P < .001). At discharge, pulmonary hypertension was associated with tracheostomy (27% vs 9%, P < .001), supplemental oxygen use (84% vs 61%, P < .001), and tube feeds (80% vs 46%, P < .001). Through 1 year of corrected age, pulmonary hypertension was associated with increased frequency of readmission (incidence rate ratio [IRR] = 1.38, 95% CI 1.18-1.63, P < .001).

CONCLUSIONS: Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through …

Can Capture Be Used To Identify Undiagnosed Patients With Mild-To-Moderate Copd Likely To Benefit From Treatment?, Nancy K. Leidy, Fernando J. Martinez, Karen G. Malley, David M. Mannino, Meilan K. Han, Elizabeth D. Bacci, Randall W. Brown, Julia F. Houfek, Wassim W. Labaki, Barry J. Make, Catherine A. Meldrum, Wilson Quezada, Stephen Rennard, Byron Thomashow, Barbara P. Yawn

Preventive Medicine and Environmental Health Faculty Publications

Background: COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE™) uses five questions and peak expiratory flow (PEF) thresholds (males ≤350 L/min; females ≤250 L/min) to identify patients with a forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC)11 60%–80% predicted) who may also benefit from diagnosis and treatment.

Methods: Data from the CAPTURE development study were used to test its sensitivity (SN) and specificity (SP) differentiating mild-to-moderate COPD (n=73) from no COPD (n=87). SN and SP for differentiating all COPD cases (mild to severe; n=259) from those without COPD (n=87) were …

Protocol For A Randomised Trial Of Higher Versus Lower Intensity Patient-Provider Communication Interventions To Reduce Antibiotic Misuse In Two Paediatric Ambulatory Clinics In The Usa., Kathy Goggin, Andrea Bradley-Ewing, Angela Myers, Brian R. Lee, Emily A. Hurley, Kirsten B. Delay, Sarah Schlachter, Areli Ramphal, Kimberly Pina, David Yu, Kirsten Weltmer, Sebastian Linnemayr, Christopher C. Butler, Jason G. Newland

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: Children with acute respiratory tract infections (ARTIs) are prescribed up to 11.4 million unnecessary antibiotic prescriptions annually. Inadequate parent-provider communication is a chief contributor, yet efforts to reduce overprescribing have only indirectly targeted communication or been impractical. This paper describes our multisite, parallel group, cluster randomised trial comparing two feasible interventions for enhancing parent-provider communication on the rate of inappropriate antibiotic prescribing (primary outcome) and revisits, adverse drug reactions and parent-rated quality of shared decision-making, parent-provider communication and visit satisfaction (secondary outcomes).

METHODS/ANALYSIS: We will attempt to recruit all eligible paediatricians and nurse practitioners (currently 47) at an academic …

Central Nervous System Histoplasmosis: Multicenter Retrospective Study On Clinical Features, Diagnostic Approach And Outcome Of Treatment, Joseph Wheat, Thein Myint, Ying Guo, Phebe Kemmer, Chadi A. Hage, Colin Terry, Marwan M. Azar, James Riddell, Peter Ender, Sharon Chen, Kareem Shehab, Kerry Cleveland, Eden Esguerra, James Johnson, Patty Wright, Vanja Douglas, Pascalis Vergidis, Winnie Ooi, John Baddley, David Bamberger, Raed N. Khairy, Holenarasipur R. Vikram, Elizabeth Jenny-Avital, Geetha Sivasubramanian, Karen Bowlware, Barbara Pahud, Juan Sarria, Townson Tsai, Maha Assi, Satish Mocherla

Internal Medicine Faculty Publications

Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report literature reviews. Therefore, a larger study of central nervous system (CNS) histoplasmosis is needed in order to guide the approach to diagnosis, and treatment.

A convenience sample of 77 patients with histoplasmosis infection of the CNS was evaluated. Data was collected that focused on recognition of infection, diagnostic techniques, and outcomes of treatment.

Twenty nine percent of patients were not immunosuppressed. Histoplasma antigen, or anti-Histoplasma antibodies were detected in the …

Imaging-Based Clusters In Current Smokers Of The Copd Cohort Associate With Clinical Characteristics: The Subpopulations And Intermediate Outcome Measures In Copd Study (Spiromics), Babak Haghighi, Sanghun Choi, Jiwoong Choi, Eric A. Hoffman, Alejandro P. Comellas, John D. Newell, R. Graham Barr, Eugene Bleecker, Christopher B. Cooper, David Couper, Mei Lan Han, Nadia N. Hansel, Richard E. Kanner, Ella A. Kazerooni, Eric A.C. Kleerup, Fernando J. Martinez, Wanda O'Neal, Stephen I. Rennard, Prescott G. Woodruff, Ching-Long Lin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD.

METHODS: Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering.

RESULTS: Four clusters …

Use Of A 4-Week Up-Titration Regimen Of Roflumilast In Patients With Severe Copd, Henrik Watz, Nitin Bagul, Klaus F. Rabe, Stephen I. Rennard, Vijay Kt Alagappan, Jonas Román, Axel Facius, Peter Ma Calverley

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy.

METHODS: In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1:1:1 to 4 weeks' treatment with ROF 250 µg once daily (OD), 500 µg every other day (EOD), or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment.

RESULTS: Patients in the 250 µg OD/500 …

Centrilobular Emphysema And Coronary Artery Calcification: Mediation Analysis In The Spiromics Cohort, Surya P. Bhatt, Hrudaya P. Nath, Young-Il Kim, Rekha Ramachandran, Jubal R. Watts, Nina L.J. Terry, Sushil Sonavane, Swati P. Deshmane, Prescott G. Woodruff, Elizabeth C. Oelsner, Sandeep Bodduluri, Meilan K. Han, Wassim W. Labaki, J. Michael Wells, Fernando J. Martinez, R. Graham Barr, Mark T. Dransfield, Spiromics Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established.

METHODS: We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used …

Can Capture Be Used To Identify Undiagnosed Patients With Mild-To-Moderate Copd Likely To Benefit From Treatment?, Nancy K. Leidy, Fernando J. Martinez, Karen G. Malley, David M. Mannino, Meilan K. Han, Elizabeth D. Bacci, Randall W. Brown, Julia F. Houfek, Wassim W. Labaki, Barry J. Make, Catherine A. Meldrum, Wilson Quezada, Stephen I. Rennard, Byron Thomashow, Barbara P. Yawn

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE™) uses five questions and peak expiratory flow (PEF) thresholds (males ≤350 L/min; females ≤250 L/min) to identify patients with a forced expiratory volume in 1 second (FEV

METHODS: Data from the CAPTURE development study were used to test its sensitivity (SN) and specificity (SP) differentiating mild-to-moderate COPD (n=73) from no COPD (n=87). SN and SP for differentiating all COPD cases (mild to severe; n=259) from those without COPD (n=87) were also estimated. The modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT™) …

The Development Of Azd7624 For Prevention Of Exacerbations In Copd: A Randomized Controlled Trial, Naimish R. Patel, Danen M. Cunoosamy, Malin Fagerås, Ziad Taib, Sara Asimus, Tove Hegelund-Myrbäck, Sofia Lundin, Katerina Pardali, Nisha Kurian, Eva Ersdal, Cecilia Kristensson, Katarina Korsback, Robert Palmér, Mary N. Brown, Steven Greenaway, Leonard Siew, Graham W. Clarke, Stephen I. Rennard, Barry J. Make, Robert A. Wise, Paul Jansson

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.

OBJECTIVES: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.

METHODS: The p38 isoform most relevant to lung inflammation was assessed …

A Novel Method Of Measuring Fractional Exhaled Nitric Oxide In Tracheostomized Ventilator-Dependent Children., Vydehi R. Murthy, Hugo Escobar, Michael Norberg, Charisse I. Lachica, Linda L. Gratny, Ashley K. Sherman, William E Truog, Winston M. Manimtim

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The lower airway concentration of fractional exhaled nitric oxide (FENO) is unknown in children with chronic lung disease of infancy who have tracheostomy for long-term mechanical ventilation. We aimed to evaluate an online method of measuring FENO in a cohort of ventilator-dependent children with a tracheostomy and to explore the relationship between the peak FENO concentration (FENO peak) and the degree of respiratory support using the respiratory severity score.

METHODS: We conducted a prospective cross-sectional study in 31 subjects who were receiving long-term respiratory support through a tracheostomy. We measured the FENO peak and FENO plateau concentration from the …

Reduced Microrna-503 Expression Augments Lung Fibroblast Vegf Production In Chronic Obstructive Pulmonary Disease, Jun Ikari, Amy J. Nelson, Jannah Obaid, Alvaro Giron-Martinez, Kumiko Ikari, Fumihiko Makino, Shunichiro Iwasawa, Yoko Gunji, Maha Farid, Xingqi Wang, Hesham Basma, Dawn Demeo, Carol Feghali-Bostwick, Olaf Holz, Klaus Rabe, Xiangde Liu, Stephen I. Rennard

Journal Articles: Pulmonary & Critical Care Med

Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without …

Variability In Objective And Subjective Measures Affects Baseline Values In Studies Of Patients With Copd, Wayne H. Anderson, Jae Wook Ha, David J. Couper, Wanda K. O'Neal, R. Graham Barr, Eugene R. Bleecker, Elizabeth E. Carretta, Christopher B. Cooper, Claire M. Doerschuk, M. Bradley Drummond, Meilan K. Han, Nadia N. Hansel, Victor Kim, Eric C. Kleerup, Fernando J. Martinez, Stephen I. Rennard, Donald Tashkin, Prescott G. Woodruff, Robert Paine, Jeffrey L. Curtis, Richard W. Kanner, Spiromics Research Group

Journal Articles: Pulmonary & Critical Care Med

RATIONALE: Understanding the reliability and repeatability of clinical measurements used in the diagnosis, treatment and monitoring of disease progression is of critical importance across all disciplines of clinical practice and in clinical trials to assess therapeutic efficacy and safety.

OBJECTIVES: Our goal is to understand normal variability for assessing true changes in health status and to more accurately utilize this data to differentiate disease characteristics and outcomes.

METHODS: Our study is the first study designed entirely to establish the repeatability of a large number of instruments utilized for the clinical assessment of COPD in the same subjects over the same …

Body Mass Index Change In Gastrointestinal Cancer And Chronic Obstructive Pulmonary Disease Is Associated With Dedicator Of Cytokinesis 1, Merry-Lynn Noelle Mcdonald, Sungho Won, Manuel Mattheisen, Peter J. Castaldi, Michael H. Cho, Erica Rutten, Megan Hardin, Wai-Ki Yip, Stephen I. Rennard, David A. Lomas, Emiel F.M. Wouters, Alvar Agusti, Richard Casaburi, Christoph P. Lange, George O'Connor, Craig P. Hersh, Edwin K. Silverman

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (ΔBMI) among cancer and COPD by using GWAS data in the Framingham Heart Study.

METHODS: A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate ΔBMI in participants over 40 years …

Network-Based Analysis Reveals Novel Gene Signatures In Peripheral Blood Of Patients With Chronic Obstructive Pulmonary Disease, Ma'en Obeidat, Yunlong Nie, Virginia Chen, Casey P. Shannon, Anand Kumar Andiappan, Bernett Lee, Olaf Rotzschke, Peter J. Castaldi, Craig P. Hersh, Nick Fishbane, Raymond T. Ng, Bruce Mcmanus, Bruce E. Miller, Stephen I. Rennard, Peter D. Paré, Don D. Sin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and there is a huge unmet clinical need to identify disease biomarkers in peripheral blood. Compared to gene level differential expression approaches to identify gene signatures, network analyses provide a biologically intuitive approach which leverages the co-expression patterns in the transcriptome to identify modules of co-expressed genes.

METHODS: A weighted gene co-expression network analysis (WGCNA) was applied to peripheral blood transcriptome from 238 COPD subjects to discover co-expressed gene modules. We then determined the relationship between these modules and forced expiratory volume in 1 s (FEV …

Indoor Tobacco Legislation Is Associated With Fewer Emergency Department Visits For Asthma Exacerbation In Children., Christina E. Ciaccio, Tami Gurley-Calvez, Theresa I. Shireman

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: During the past 3 decades, numerous cities and states have adopted laws that ban smoking in public indoor spaces. The rationale for these policies has been to protect nonsmokers from the adverse health effects of secondhand smoke.

OBJECTIVE: To determine whether the implementation of indoor smoking legislation is associated with a decrease in emergency department visits for asthma in children.

METHODS: This retrospective analysis used a natural experiment to estimate the impact of clean indoor air legislation on the rate of emergency department admissions for asthma exacerbation in children. Data were obtained from the Pediatric Health Information System. A …

Development Of A Spirometry T-Score In The General Population, Sei Won Lee, Hyun Kuk Kim, Seunghee Baek, Ji-Ye Jung, Young Sam Kim, Jae Seung Lee, Sang-Do Lee, David M. Mannino, Yeon-Mok Oh

Preventive Medicine and Environmental Health Faculty Publications

Background and objective: Spirometry values may be expressed as T-scores in standard deviation units relative to a reference in a young, normal population as an analogy to the T-score for bone mineral density. This study was performed to develop the spirometry T-score.

Methods: T-scores were calculated from lambda-mu-sigma-derived Z-scores using a young, normal age reference. Three outcomes of all-cause death, respiratory death, and COPD death were evaluated in 9,101 US subjects followed for 10 years; an outcome of COPD-related health care utilization (COPD utilization) was evaluated in 1,894 Korean subjects followed for 4 years.

Results: The …

Effects Of Roflumilast In Copd Patients Receiving Inhaled Corticosteroid/Long-Acting Β2-Agonist Fixed-Dose Combination: Re(2)Spond Rationale And Study Design, Stephen I. Rennard, Fernando J. Martinez, Klaus F. Rabe, Sanjay Sethi, Emilio Pizzichini, Andrew Mcivor, Shahid Siddiqui, Antonio Anzueto, Haiyuan Zhu

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Roflumilast, a once-daily, selective phosphodiesterase-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. The RE(2)SPOND study is examining whether roflumilast, when added to an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) fixed-dose combination (FDC), further reduces exacerbations. The methodology is described herein.

METHODS: In this Phase IV, multicenter, double-blind, placebo-controlled, parallel-group trial, participants were randomized 1:1 (stratified by long-acting muscarinic antagonist use) to receive roflumilast or placebo, plus ICS/LABA FDC, for 52 weeks. Eligible participants had severe COPD associated with chronic bronchitis, had two or more moderate-severe exacerbations within …

Copd Exacerbation Biomarkers Validated Using Multiple Reaction Monitoring Mass Spectrometry, Janice M. Leung, Virginia Chen, Zsuzsanna Hollander, Darlene Dai, Scott J. Tebbutt, Shawn D. Aaron, Kathy L. Vandemheen, Stephen I. Rennard, J. Mark Fitzgerald, Prescott G. Woodruff, Stephen C. Lazarus, John E. Connett, Harvey O. Coxson, Bruce Miller, Christoph Borchers, Bruce M. Mcmanus, Raymond T. Ng, Don D. Sin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD.

METHODS: We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72). Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate < 0.01 and fold change >1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel …

Effect Of Tiotropium On Night-Time Awakening And Daily Rescue Medication Use In Patients With Copd, Peter M.A. Calverley, Stephen I. Rennard, Emmanuelle Clerisme-Beaty, Norbert Metzdorf, Valentina Bayer Zubek, Richard Zuwallack

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Several small studies found night-time awakenings due to COPD symptoms were associated with decreased health status. In this study, night-time awakenings in patients with COPD were examined and effects of tiotropium therapy evaluated.

METHODS: This study was a post hoc, exploratory, pooled analysis of twin, multicenter, double-blind, randomized, placebo-controlled, parallel-group trials. Patients with stable moderate-to-severe COPD were randomized to tiotropium HandiHaler® (n = 550) or placebo (n = 371) and followed for 13 weeks. During a 2-week, pre-treatment baseline period and for 13 weeks on treatment, self-reported night-time awakenings due to COPD symptoms, rescue medication (albuterol) use, and morning …

Identifying Cases Of Undiagnosed, Clinically Significant Copd In Primary Care: Qualitative Insight From Patients In The Target Population, Nancy K. Leidy, Katherine Kim, Elizabeth D. Bacci, Barbara P. Yawn, David M. Mannino, Byron M. Thomashow, R. Graham Barr, Stephen I. Rennard, Julia F. Houfek, Meilan K. Han, Catherine A. Meldrum, Barry J. Make, Russ P. Bowler, Anna W. Steenrod, Lindsey T. Murray, John W. Walsh, Fernando Martinez, High-Risk-Copd Screening Study Group

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Many cases of chronic obstructive pulmonary disease (COPD) are diagnosed only after significant loss of lung function or during exacerbations.

AIMS: This study is part of a multi-method approach to develop a new screening instrument for identifying undiagnosed, clinically significant COPD in primary care.

METHODS: Subjects with varied histories of COPD diagnosis, risk factors and history of exacerbations were recruited through five US clinics (four pulmonary, one primary care). Phase I: Eight focus groups and six telephone interviews were conducted to elicit descriptions of risk factors for COPD, recent or historical acute respiratory events, and symptoms to inform the …

The Effect Of Statins On Blood Gene Expression In Copd, Ma'en Obeidat, Nick Fishbane, Yunlong Nie, Virginia Chen, Zsuzsanna Hollander, Scottj Tebbutt, Yohan Bossé, Raymond T. Ng, Bruce E. Miller, Bruce Mcmanus, Stephen I. Rennard, Peter D. Paré, Don D. Sin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: COPD is currently the fourth leading cause of death worldwide. Statins are lipid lowering agents with documented cardiovascular benefits. Observational studies have shown that statins may have a beneficial role in COPD. The impact of statins on blood gene expression from COPD patients is largely unknown.

OBJECTIVE: Identify blood gene signature associated with statin use in COPD patients, and the pathways underpinning this signature that could explain any potential benefits in COPD.

METHODS: Whole blood gene expression was measured on 168 statin users and 451 non-users from the ECLIPSE study using the Affymetrix Human Gene 1.1 ST microarray chips. …

Identifying A Gene Expression Signature Of Frequent Copd Exacerbations In Peripheral Blood Using Network Methods, Jarrett D. Morrow, Weiliang Qiu, Divya Chhabra, Stephen I. Rennard, Paula Belloni, Anton Belousov, Sreekumar G. Pillai, Craig P. Hersh

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility. Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations.

METHODS: Gene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) …

Non-Emphysematous Chronic Obstructive Pulmonary Disease Is Associated With Diabetes Mellitus, Craig P. Hersh, Barry J. Make, David A. Lynch, R. Graham Barr, Russell P. Bowler, Peter M.A. Calverley, Peter J. Castaldi, Michael H. Cho, Harvey O. Coxson, Dawn L. Demeo, Marilyn G. Foreman, Meilan K. Han, Benjamin J. Harshfield, John E. Hokanson, Sharon Lutz, Joe W. Ramsdell, Elizabeth A. Regan, Stephen I. Rennard, Joyce D. Schroeder, Frank C. Sciurba, Robert M. Steiner, Ruth Tal-Singer, Edwin Van Beek, Edwin K. Silverman, James D. Crapo, Copdgene And Eclipse Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients.

METHODS: Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 …

Sexually-Dimorphic Targeting Of Functionally-Related Genes In Copd, Kimberly Glass, John Quackenbush, Edwin K. Silverman, Bartolome Celli, Stephen I. Rennard, Guo-Cheng Yuan, Dawn L. Demeo

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism.

RESULTS: Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack-knifing approach to …

The Association Of Plasma Biomarkers With Computed Tomography-Assessed Emphysema Phenotypes, Brendan J. Carolan, Grant Hughes, Jarrett Morrow, Craig P. Hersh, Wanda K. O'Neal, Stephen I. Rennard, Sreekumar G. Pillai, Paula Belloni, Debra A. Cockayne, Alejandro P. Comellas, Meilan Han, Rachel L. Zemans, Katerina Kechris, Russell P. Bowler

Journal Articles: Pulmonary & Critical Care Med

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a phenotypically heterogeneous disease. In COPD, the presence of emphysema is associated with increased mortality and risk of lung cancer. High resolution computed tomography (HRCT) scans are useful in quantifying emphysema but are associated with radiation exposure and high incidence of false positive findings (i.e., nodules). Using a comprehensive biomarker panel, we sought to determine if there was a peripheral blood biomarker signature of emphysema.

METHODS: 114 plasma biomarkers were measured using a custom assay in 588 individuals enrolled in the COPDGene study. Quantitative emphysema measurements included percent low lung attenuation (%LAA) ≤ …

Randomized Study Of The Safety, Pharmacokinetics, And Bronchodilatory Efficacy Of A Proprietary Glycopyrronium Metered-Dose Inhaler In Study Patients With Chronic Obstructive Pulmonary Disease, Stephen I. Rennard, Charles Fogarty, Colin Reisner, Carlos Fernandez, Tracy Fischer, Michael Golden, Earl St Rose, Patrick Darken, Gregory Tardie, Chadwick Orevillo

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers.

METHODS: In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of …

Clinical And Computed Tomographic Predictors Of Chronic Bronchitis In Copd: A Cross Sectional Analysis Of The Copdgene Study, Victor Kim, Adam Davey, Alejandro P. Comellas, Meilan K. Han, George Washko, Carlos H. Martinez, David Lynch, Jin Hwa Lee, Edwin K. Silverman, James D. Crapo, Barry J. Make, Gerard J. Criner, The Copdgene® Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic bronchitis (CB) has been related to poor outcomes in Chronic Obstructive Pulmonary Disease (COPD). From a clinical standpoint, we have shown that subjects with CB in a group with moderate to severe airflow obstruction were younger, more likely to be current smokers, male, Caucasian, had worse health related quality of life, more dyspnea, and increased exacerbation history compared to those without CB. We sought to further refine our clinical characterization of chronic bronchitics in a larger cohort and analyze the CT correlates of CB in COPD subjects. We hypothesized that COPD patients with CB would have thicker airways …