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1.  Interstitial Lung Disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases 
Annals of the American Thoracic Society  2014;11(Suppl 3):S169-S177.
Population-based, longitudinal studies spanning decades linking risk factors in childhood, adolescence and early adulthood to incident clinical interstitial lung disease (ILD) events in late adulthood have not been performed. In addition, no observational or randomized clinical trials have been conducted; therefore, there is presently no evidence to support the notion that reduction of risk factor levels in early life prevents ILD events in adult life. Primary prevention strategies are host-directed interventions designed to modify adverse risk factors (i.e., smoking) with the goal of preventing the development of ILD, whereas primordial prevention for ILD can be defined as the elimination of external risk factors (i.e., environmental pollutants). As no ILD primary prevention studies have been previously conducted, we propose that research studies that promote implementation of primary prevention strategies could, over time, make a subset of ILD preventable. Herein, we provide a number of initial steps required for the future implementation of prevention strategies; this statement discusses the rationale and available evidence that support potential opportunities for primordial and primary prevention, as well as fertile areas for future research of preventive intervention in ILD.
doi:10.1513/AnnalsATS.201312-429LD
PMCID: PMC4112506  PMID: 24754826
pulmonary fibrosis; prevention
2.  Smoking related idiopathic interstitial pneumonia: Results of an ERS/ATS Task Force 
The European respiratory journal  2014;44(3):594-602.
Background
Cigarette smoking is a key factor in the development of numerous pulmonary diseases.
Methods
An international group of clinicians, radiologists, and pathologists evaluated patients with previously identified idiopathic interstitial pneumonia (IIP) to determine unique features of cigarette smoking. Phase 1 (derivation group) identified smoking related features in patients with a history of smoking (n=41). Phase 2 (validation group) determined if these features correctly predicted the smoking status of IIP patients (n=100) to participants blinded to smoking history. Finally, investigators sought to determine if a new smoking-related interstitial lung disease phenotype could be defined.
Results
Phase 1 suggested that preserved forced vital capacity with disproportionately reduced DLCO, various radiographic and histopathologic findings were smoking related features. In Phase 2 the kappa among clinicians was 0.16 (95% CI 0.11 – 0.21), among the pathologists 0.36 (95% CI 0.32 – 0.34) and among the radiologists 0.43 (95% CI 0.35 – 0.52) for smoking related features. Eight of the 100 cases were felt to represent a potential smoking related interstitial lung disease.
Conclusion
Smoking related features of interstitial lung disease were identified in a minority of smokers and are not specific for smoking. This study is limited by its retrospective design and the potential for recall bias of smoking history and lack of information on second had smoke exposure. Further research is needed to understand the relationship between smoking and interstitial lung disease.
doi:10.1183/09031936.00166813
PMCID: PMC4366053  PMID: 25063244
computed tomography; histopathology; interstitial lung disease; smoking
3.  Inflammatory Leukocyte Phenotypes Correlate with Disease Progression in Idiopathic Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive deposition of extracellular matrix, worsening dyspnea, and eventual mortality. Pathogenesis of IPF is poorly understood and the role inflammation and activated leukocytes play in the disease process is controversial. Previous studies demonstrated that activated leukocyte subsets characterize IPF patients. We sought to validate this observation in a well-defined cohort of 35 IPF patients and to correlate the observed leukocyte phenotypes with robust parameters of disease progression. We demonstrate that in univariate and multivariate analyses, increases in the CD14hi, CD16hi subset of monocytes measured at baseline correlated with disease progression, with a threshold value >0.5% of the total peripheral blood mononuclear cells being a significant predictor for worse outcome. In addition, several T cell subsets, including CD25 expressing CD4 cells, and CXCR3 expressing CD4 and CD8 subsets correlated with disease progression when found in increased percentages in the peripheral blood of IPF patients when sampled at baseline. Somewhat surprising in comparison to previous literature, the CD4 T cells did not appear to have lost expression of the co-stimulatory molecule, CD28, but the CD8 T cells did. Taken together, these results are consistent with the presence of an inflammatory process in IPF patients who eventually progress. However, when longitudinal measurements of these same markers were examined, there was significant heterogeneity of expression and these biomarkers did not necessarily remain elevated in IPF patients with progressive disease. We interpret this heterogeneity to suggest that IPF patients experience episodic inflammatory events that once triggered, may lead to disease progression. This longitudinal heterogeneity in biomarker analyses may explain why such markers are not consistently measured in all IPF cohorts.
doi:10.3389/fmed.2014.00056
PMCID: PMC4286285  PMID: 25580363
lung; lymphocyte; monocyte; interstitial lung disease; peripheral blood
4.  Identifying Patients with Undiagnosed COPD in Primary Care Settings: Insight from Screening Tools and Epidemiologic Studies 
Objective
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, yet research suggests this disease is greatly underdiagnosed. This literature review sought to summarize the most common and significant variables associated with case-finding or missed cases of COPD to inform more effective and efficient detection of high-risk COPD patients in primary care.
Methods
PubMed and EMBASE were searched for articles describing case-finding and epidemiologic research to detect or characterize new cases of COPD. International studies in primary and non-primary care settings, published in English from 2002–2014, were eligible for inclusion. Studies related to risk factors for development of COPD were excluded.
Results
Of the 33 studies identified and reviewed, 21 were case-finding or screening and 12 were epidemiological, including cross-sectional, longitudinal, and retrospective designs. A range of variables were identified within and across studies. Variables common to both screening and epidemiological studies included age, smoking status, and respiratory symptoms. Seven significant predictors from epidemiologic studies did not appear in screening tools. No studies targeted discovery of higher risk patients such as those with reduced lung function or risks for exacerbations.
Conclusion
Variables used to identify new cases of COPD or differentiate COPD cases and non-cases are wide- ranging, (from sociodemographic to self-reported health or health history variables), providing insight into important factors for case identification. Further research is underway to develop and test the best, smallest variable set that can be used as a screening tool to identify people with undiagnosed, high-risk COPD in primary care.
doi:10.15326/jcopdf.2.2.2014.0152
PMCID: PMC4521771
chronic obstructive pulmonary disease; primary care; screening; literature review
5.  Association Between Lung Microbiome and Disease Progression in IPF: A Prospective Cohort Study 
The Lancet. Respiratory medicine  2014;2(7):548-556.
Background
The lung microbiome’s contribution to IPF pathogenesisis unknown. Using COMET-IPF (Correlating Outcomes with biochemical Markers to Estimate Time-progression in Idiopathic Pulmonary Fibrosis), the goal of this study was to determine whether unique microbial signatures would associate with disease progression.
Methods
IPF subjects within four years of diagnosis aged 35–80 were eligible for inclusion. Subjects were followed for up to a maximum of 80 weeks. This completed observational study is registered with ClinicalTrials.gov, number NCT01071707. Progression-free survival was defined as death, acute exacerbation, lung transplant, or decline in FVC of 10% or DLCO of 15%.DNA was isolated from 55 bronchoscopic alveolar lavage (BAL) samples. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) based on a 3% sequence divergence. Adjusted Cox models identified OTUs significantly associated with progression-free survival at a p<0·10 level. These OTUs were then used in principal components (PC) analysis. The association between PCs and microbes with high factor loadings from the PC analysis and progression-free survival were examined via Cox regression analyses.
Findings
Mean FVC was 70·1% and mean DLCO 42·3 %predicted. Significant associations with disease progression were noted with increased % relative abundance of two OTUs identified by PC analysis, a Streptococcus OTU. (p<0·0009) and a Staphylococcus OTU(p=0·01). Strength of associations using PCs versus two OTUs alone was similar. Threshold analysis helped define a cut point for % relative abundance for each OTU associated with progression-free survival, >3·9% for the Streptococcus OTU, HR 10·19 (95% CI 2·94, 35·35; p=0·0002) and >1·8% for the Staphylococcus OTU, HR 5·06 (1·71, 14·93; p=0·003).
Interpretation
These preliminary data suggest IPF disease progression is associated with presence of specific members within the Staphylococcus and Streptococcus genera.
doi:10.1016/S2213-2600(14)70069-4
PMCID: PMC4142525  PMID: 24767767
6.  Predictors of Chronic Obstructive Pulmonary Disease Exacerbation Reduction in Response to Daily Azithromycin Therapy 
Rationale: Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown.
Objectives: To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care.
Methods: Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use.
Measurements and Main Results: Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71–1.38; P = 0.95).
Conclusions: Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers.
Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).
doi:10.1164/rccm.201402-0207OC
PMCID: PMC4226018  PMID: 24779680
chronic obstructive pulmonary disease; exacerbation; quality of life; azithromycin
7.  DESIGN OF THE SUBPOPULATIONS AND INTERMEDIATE OUTCOMES IN COPD STUDY (SPIROMICS) 
Thorax  2013;69(5):492-495.
SPIROMICS is a multi-center observational study of chronic obstructive pulmonary disease (COPD) designed to guide future development of therapies for COPD by 1) providing robust criteria for sub-classifying COPD participants into groups most likely to benefit from a given therapy during a clinical trial, thereby improving the chances of successful outcome; and 2) identifying biomarkers/phenotypes that can be used as intermediate outcomes to reliably predict clinical benefit during therapeutic trials, thus reducing costs. The goal is to enroll 3,200 participants in four strata: severe COPD, mild/moderate COPD, smokers without airflow obstruction and non-smoking controls. Participants undergo a baseline visit including morphometric measures, spirometry, six-minute walk, an inspiratory and expiratory chest CT, and a set of standardized questionnaires. Biospecimens, including plasma, serum, DNA, urine and induced sputum, are collected and stored. There are three annual follow-up examinations, with quarterly telephone calls to assess for exacerbations, hospitalizations and mortality. Bronchoscopy is being performed in a subset of participants and a subset of COPD patients will be assessed during exacerbations. Adjudication of exacerbations and mortality will be undertaken. SPIROMICS is designed so that sub-studies and ancillary studies testing additional hypotheses can be added.
doi:10.1136/thoraxjnl-2013-203897
PMCID: PMC3954445  PMID: 24029743
COPD Exacerbations; Emphysema; Imaging/CT MRI etc; COPD epidemiology
8.  Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model 
The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung.
doi:10.1165/rcmb.2013-0342OC
PMCID: PMC4068948  PMID: 24325475
fibroblast; epithelium; fibrosis
9.  Heart Failure and Respiratory Hospitalizations Are Reduced in Patients With Heart Failure and Chronic Obstructive Pulmonary Disease With the Use of an Implantable Pulmonary Artery Pressure Monitoring Device 
Journal of cardiac failure  2014;21(3):240-249.
Background
Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). Elevated pulmonary arterial (PA) pressure can be seen in both conditions and has been shown to predict morbidity and mortality.
Methods and Results
A total of 550 subjects with New York Heart Association functional class III HF were randomly assigned to the treatment (n = 270) and control (n = 280) groups in the CHAMPION Trial. Physicians had access to the PA pressure measurements in the treatment group only, in which HF therapy was used to lower the elevated pressures. HF and respiratory hospitalizations were compared in both groups. A total of 187 subjects met criteria for classification into the COPD subgroup. In the entire cohort, the treatment group had a 37% reduction in HF hospitalization rates (P < .0001) and a 49% reduction in respiratory hospitalization rates (P = .0061). In the COPD subgroup, the treatment group had a 41% reduction in HF hospitalization rates (P = .0009) and a 62% reduction in respiratory hospitalization rates (P = .0023). The rate of respiratory hospitalizations in subjects without COPD was not statistically different (P = .76).
Conclusions
HF management incorporating hemodynamic information from an implantable PA pressure monitor significantly reduces HF and respiratory hospitalizations in HF subjects with comorbid COPD compared with standard care.
doi:10.1016/j.cardfail.2014.12.008
PMCID: PMC4405122  PMID: 25541376
Heart failure; chronic obstructive pulmonary disease; implantable pulmonary artery pressure monitor; hospitalization
10.  Longitudinal Change in the BODE Index Predicts Mortality in Severe Emphysema 
Rationale: The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients.
Objectives: To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival.
Methods: Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components.
Measurements and Main Results: The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components.
Conclusions: The mBODE demonstrates short- and intermediate-term responsiveness to intervention in severe chronic obstructive pulmonary disease. Increase in mBODE of more than 1 point from baseline to 6, 12, and 24 months of follow-up was predictive of subsequent mortality. Change in mBODE may prove a good surrogate measure of survival in therapeutic trials in severe chronic obstructive pulmonary disease.
Clinical trial registered with www.clinicaltrials.gov (NCT 00000606).
doi:10.1164/rccm.200709-1383OC
PMCID: PMC2542428  PMID: 18535255
chronic obstructive pulmonary disease; survival; multidimensional index
11.  Analysis of Culture-Dependent versus Culture-Independent Techniques for Identification of Bacteria in Clinically Obtained Bronchoalveolar Lavage Fluid 
Journal of Clinical Microbiology  2014;52(10):3605-3613.
The diagnosis and management of pneumonia are limited by the use of culture-based techniques of microbial identification, which may fail to identify unculturable, fastidious, and metabolically active viable but unculturable bacteria. Novel high-throughput culture-independent techniques hold promise but have not been systematically compared to conventional culture. We analyzed 46 clinically obtained bronchoalveolar lavage (BAL) fluid specimens from symptomatic and asymptomatic lung transplant recipients both by culture (using a clinical microbiology laboratory protocol) and by bacterial 16S rRNA gene pyrosequencing. Bacteria were identified in 44 of 46 (95.7%) BAL fluid specimens by culture-independent sequencing, significantly more than the number of specimens in which bacteria were detected (37 of 46, 80.4%, P ≤ 0.05) or “pathogen” species reported (18 of 46, 39.1%, P ≤ 0.0001) via culture. Identification of bacteria by culture was positively associated with culture-independent indices of infection (total bacterial DNA burden and low bacterial community diversity) (P ≤ 0.01). In BAL fluid specimens with no culture growth, the amount of bacterial DNA was greater than that in reagent and rinse controls, and communities were markedly dominated by select Gammaproteobacteria, notably Escherichia species and Pseudomonas fluorescens. Culture growth above the threshold of 104 CFU/ml was correlated with increased bacterial DNA burden (P < 0.01), decreased community diversity (P < 0.05), and increased relative abundance of Pseudomonas aeruginosa (P < 0.001). We present two case studies in which culture-independent techniques identified a respiratory pathogen missed by culture and clarified whether a cultured “oral flora” species represented a state of acute infection. In summary, we found that bacterial culture of BAL fluid is largely effective in discriminating acute infection from its absence and identified some specific limitations of BAL fluid culture in the diagnosis of pneumonia. We report the first correlation of quantitative BAL fluid culture results with culture-independent evidence of infection.
doi:10.1128/JCM.01028-14
PMCID: PMC4187760  PMID: 25078910
12.  Natural History of Emphysema 
Chronic obstructive pulmonary disease (COPD) is a progressive disease with studies of disease progression generally focusing on measures of airflow and mortality. In nonsmokers, maximal lung function is attained around age 15 to 25 years, and after a variable plateau phase, subsequently declines at approximately 20 to 25 ml/year. Smoking may reduce the maximal FEV1 achieved, shorten or eliminate the plateau phase, and may accelerate the rate of decline in lung function in a dose-dependent manner. Some smokers are predisposed to more rapid declines in lung function than others, and recent reports suggest that females may be at higher risk of lung damage related to smoke exposure than males. Progressive deterioration in dyspnea, functional status, and health-related quality of life (HRQL) in patients with COPD is well known, but the magnitude and rate of decline and its association with severity of airflow obstruction remains poorly defined. Many studies have identified pulmonary function, in particular the FEV1, as the single best predictor of survival. An impaired diffusing capacity and overall impairment in functional status have also been associated with impaired survival in COPD. The National Emphysema Treatment Trial has provided additional insight into these features in a large, well-characterized group of patients with severe airflow obstruction and structural emphysema.
doi:10.1513/pats.200802-018ET
PMCID: PMC2645321  PMID: 18453357
emphysema; natural history; survival; pulmonary function; quality of life
13.  Gender and Chronic Obstructive Pulmonary Disease 
The prevalence of chronic obstructive pulmonary disease (COPD) in women is increasing, as is hospitalization for COPD. The number of women dying of COPD in the United States now surpasses men. Despite this, research suggests that physicians are still more likely to correctly diagnose men with COPD than women. Increased tobacco use in women likely explains some of the increase in the prevalence of COPD in women, but data suggest that women may actually be at greater risk of smoking-induced lung function impairment, more severe dyspnea, and poorer health status for the same level of tobacco exposure. The degree to which these observations represent biologic, physiologic, or sociologic differences is not known. Nonsmokers with COPD are also more likely to be female. In addition, new evidence is emerging that men and women may be phenotypically different in their response to tobacco smoke, with men being more prone to an emphysematous phenotype and women an airway predominant phenotype. Inasmuch as COPD is a disease of inflammation, it is also possible that sexual dimorphism of the human immune response may also be responsible for gender differences in the disease. More data are still needed on what the implications of these findings are on therapy. In this clinical commentary, we present current knowledge regarding how gender influences the epidemiology, diagnosis, and presentation of COPD in addition to physiologic and psychologic impairments and we attempt to offer insight into why these differences might exist and how this may influence therapeutic management.
doi:10.1164/rccm.200704-553CC
PMCID: PMC2720110  PMID: 17673696
tobacco susceptibility; smoking; sex; obstructive lung disease
14.  Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease 
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural history of this chronic lung disorder. These events can be caused by a large number of infectious and noninfectious agents and are associated with an increased local and systemic inflammatory response. Their frequency and severity have been linked to progressive deterioration in lung function and health status. Infectious pathogens ranging from viral to atypical and typical bacteria have been implicated in the majority of episodes. Most therapeutic regimens to date have emphasized broad, nonspecific approaches to bronchoconstriction and pulmonary inflammation. Increasingly, therapy that targets specific etiologic pathogens has been advocated. These include clinical and laboratory-based methods to identify bacterial infections. Further additional investigation has suggested specific pathogens within this broad class. As specific antiviral therapies become available, better diagnostic approaches to identify specific pathogens will be required. Furthermore, prophylactic therapy for at-risk individuals during high-risk times may become a standard therapeutic approach. As such, the future will likely include aggressive diagnostic algorithms based on the combination of clinical syndromes and rapid laboratory modalities to identify specific causative bacteria or viruses.
doi:10.1513/pats.200707-097TH
PMCID: PMC2647652  PMID: 18073397
chronic obstructive pulmonary disease; acute exacerbations; virus; bacteria; therapy
15.  Role of macrolide therapy in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability worldwide. The Global Burden of Disease study has concluded that COPD will become the third leading cause of death worldwide by 2020, and will increase its ranking of disability-adjusted life years lost from 12th to 5th. Acute exacerbations of COPD (AECOPD) are associated with impaired quality of life and pulmonary function. More frequent or severe AECOPDs have been associated with especially markedly impaired quality of life and a greater longitudinal loss of pulmonary function. COPD and AECOPDs are characterized by an augmented inflammatory response. Macrolide antibiotics are macrocyclical lactones that provide adequate coverage for the most frequently identified pathogens in AECOPD and have been generally included in published guidelines for AECOPD management. In addition, they exert broad-ranging, immunomodulatory effects both in vitro and in vivo, as well as diverse actions that suppress microbial virulence factors. Macrolide antibiotics have been used to successfully treat a number of chronic, inflammatory lung disorders including diffuse panbronchiolitis, asthma, noncystic fibrosis associated bronchiectasis, and cystic fibrosis. Data in COPD patients have been limited and contradictory but the majority hint to a potential clinical and biological effect. Additional, prospective, controlled data are required to define any potential treatment effect, the nature of this effect, and the role of bronchiectasis, baseline colonization, and other cormorbidities.
PMCID: PMC2629987  PMID: 18990961
macrolide therapy; antibiotics; AECOPD
16.  THE CLINICAL IMPACT OF NON-OBSTRUCTIVE CHRONIC BRONCHITIS IN CURRENT AND FORMER SMOKERS 
Respiratory medicine  2013;108(3):491-499.
Background
As the clinical significance of chronic bronchitis among smokers without airflow obstruction is unclear, we sought to determine morbidity associated with this disorder.
Methods
We examined subjects from the COPDGene study and compared those with FEV1/FVC ≥0.70, no diagnosis of asthma and chronic bronchitis as defined as a history of cough and phlegm production for ≥3 months/year for ≥2 years (NCB) to non-obstructed subjects without chronic bronchitis (CB−). Multivariate analysis was used to determine factors associated with and impact of NCB.
Results
We identified 597 NCB and 4,283 CB− subjects. NCB participants were younger (55.4 vs. 57.2 years, p<0.001) with greater tobacco exposure (42.9 vs. 37.8 pack-years, p<0.001) and more often current smokers; more frequently reported occupational exposure to fumes (52.8% vs. 42.2%, p<0.001), dust for ≥1 year (55.3% vs. 42.0%, p<0.001) and were less likely to be currently working. NCB subjects demonstrated worse quality-of-life (SGRQ 35.6 vs. 15.1, p<0.001) and exercise capacity (walk distance 415 vs. 449 m, p<0.001) and more frequently reported respiratory “flare-ups” requiring treatment with antibiotics or steroids (0.30 vs. 0.10 annual events/subject, p<0.001) prior to enrollment and during follow-up (0.34 vs. 0.16 annual events/subject, p<0.001). In multivariate analysis, current smoking, GERD, sleep apnea and occupational exposures were significantly associated with NCB.
Conclusions
While longitudinal data will be needed to determine whether NCB progresses to COPD, NCB patients have poorer quality-of-life, exercise capacity and frequent respiratory events. Beyond smoking cessation interventions, further research is warranted to determine the benefit of other therapeutics in this population.
doi:10.1016/j.rmed.2013.11.003
PMCID: PMC3943716  PMID: 24280543
Cough; quality of life; gastroesophageal reflux; occupational exposure; GERD; tobacco
17.  Sex Differences in Severe Pulmonary Emphysema 
Rationale: Limited data on sex differences in advanced COPD are available.
Objectives: To compare male and female emphysema patients with severe disease.
Methods: One thousand fifty-three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National Emphysema Treatment Trial were analyzed.
Measurements and Main Results: Detailed clinical, physiological, and radiological assessment, including quantitation of emphysema severity and distribution from helical chest computed tomography, was completed. In a subgroup (n = 101), airway size and thickness was determined by histological analyses of resected tissue. Women were younger and exhibited a lower body mass index (BMI), shorter smoking history, less severe airflow obstruction, lower Dlco and arterial Po2, higher arterial Pco2, shorter six-minute walk distance, and lower maximal wattage during oxygen-supplemented cycle ergometry. For a given FEV1% predicted, age, number of pack-years, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE, more depression, lower SF-36 mental component score, and lower quality of well-being. Overall emphysema was less severe in women, with the difference from men most evident in the outer peel of the lung. Females had thicker small airway walls relative to luminal perimeters.
Conclusions: In patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.
doi:10.1164/rccm.200606-828OC
PMCID: PMC1994221  PMID: 17431226
chronic obstructive pulmonary disease; emphysema; computed tomography; pulmonary function; gender
18.  Development and Initial Validation of a Self-Scored COPD Population Screener Questionnaire (COPD-PS) 
COPD  2008;5(2):85-95.
COPD has a profound impact on daily life, yet remains underdiagnosed and undertreated. We set out to develop a brief, reliable, self-scored questionnaire to identify individuals likely to have COPD. COPD-PS™ development began with a list of concepts identified for inclusion using expert opinion from a clinician working group comprised of pulmonologists (n = 5) and primary care clinicians (n = 5). A national survey of 697 patients was conducted at 12 practitioner sites. Logistic regression identified items discriminating between patients with and without fixed airflow obstruction (AO, postbronchodilator FEV1/FVC < 70%). ROC analyses evaluated screening accuracy, compared scoring options, and assessed concurrent validity. Convergent and discriminant validity were assessed via COPD-PS and SF-12v2 score correlations. For known-groups validation, COPD-PS differences between clinical groups were tested. Test-retest reliability was evaluated in a 20% sample. Of 697 patients surveyed, 295 patients met expert review criteria for spirometry performance; 38% of these (n = 113) had results indicating AO. Five items positively predicted AO (p < 0.0001): breathlessness, productive cough, activity limitation, smoking history, and age. COPD-PS scores accurately classified AO status (area under ROC curve = 0.81) and reliable (r = 0.91). Patients with spirometry indicative of AO scored significantly higher (6.8, SD = 1.9; p < 0.0001) than patients without AO (4.0, SD = 2.3). Higher scores were associated with more severe AO, bronchodilator use, and overnight hospitalization for breathing problems. With the prevalence of COPD in the studied cohort, a score on the COPD-PS of greater than five was associated with a positive predictive value of 56.8% and negative predictive value of 86.4%. The COPD-PS accurately classified physician-reported COPD (AUC = 0.89). The COPD-PS is a brief, accurate questionnaire that can identify individuals likely to have COPD.
doi:10.1080/15412550801940721
PMCID: PMC2430173  PMID: 18415807
Pulmonary Disease; Chronic Obstructive; Spirometry; Health Survey; Questionnaire; Screening
19.  The Role of the Microbiome in Exacerbations of Chronic Lung Diseases 
Lancet  2014;384(9944):691-702.
Summary
Culture-independent microbiological techniques have revealed a previously unappreciated complexity to the bacterial microbiome of the respiratory tract, forcing reconsideration of the interactions between host, bacteria and the pathogenesis of exacerbations of chronic lung disease. The composition of the lung microbiome is determined by microbial immigration, elimination, and the relative growth rates of its members; all of these change dramatically in chronic lung disease and further during exacerbations. Exacerbations lack key features of bacterial infections, including increased bacterial burden and decreased community diversity. We propose instead that exacerbations are occasions of respiratory dysbiosis: a disordered respiratory microbial ecosystem with negative effects on host biology. Respiratory dysbiosis provokes a dysregulated host immune response, which in turn alters microbial growth conditions in patient airways, further promoting dysbiosis and perpetuating a coupled cycle of inflammation and disordered microbiota. Differences in baseline respiratory microbiota may help explain the “frequent-exacerbator” phenotype observed across multiple disease states, and may provide novel targets for therapeutic intervention.
doi:10.1016/S0140-6736(14)61136-3
PMCID: PMC4166502  PMID: 25152271
20.  Acute Exacerbations of Idiopathic Pulmonary Fibrosis 
The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
doi:10.1164/rccm.200703-463PP
PMCID: PMC2094133  PMID: 17585107
acute exacerbation; pulmonary fibrosis; diagnosis; definition
21.  Predictors of Mortality in Patients with Emphysema and Severe Airflow Obstruction 
Purpose: Limited data exist describing risk factors for mortality in patients having predominantly emphysema.
Subjects and Methods: A total of 609 patients with severe emphysema (ages 40–83 yr; 64.2% male) randomized to the medical therapy arm of the National Emphysema Treatment Trial formed the study group. Cox proportional hazards regression analysis was used to investigate risk factors for all-cause mortality. Risk factors examined included demographics, body mass index, physiologic data, quality of life, dyspnea, oxygen utilization, hemoglobin, smoking history, quantitative emphysema markers on computed tomography, and a modification of a recently described multifunctional index (modified BODE).
Results: Overall, high mortality was seen in this cohort (12.7 deaths per 100 person-years; 292 total deaths). In multivariate analyses, increasing age (p = 0.001), oxygen utilization (p = 0.04), lower total lung capacity % predicted (p = 0.05), higher residual volume % predicted (p = 0.04), lower maximal cardiopulmonary exercise testing workload (p = 0.002), greater proportion of emphysema in the lower lung zone versus the upper lung zone (p = 0.005), and lower upper-to-lower-lung perfusion ratio (p = 0.007), and modified BODE (p = 0.02) were predictive of mortality. FEV1 was a significant predictor of mortality in univariate analysis (p = 0.005), but not in multivariate analysis (p = 0.21).
Conclusion: Although patients with advanced emphysema experience significant mortality, subgroups based on age, oxygen utilization, physiologic measures, exercise capacity, and emphysema distribution identify those at increased risk of death.
doi:10.1164/rccm.200510-1677OC
PMCID: PMC2662972  PMID: 16543549
chronic obstructive pulmonary disease; computed tomography; mortality; prognosis; pulmonary function
22.  Pulmonary Function Testing in Idiopathic Interstitial Pneumonias 
Diffuse parenchymal lung diseases are a group of disorders that involve the space between the epithelial and endothelial basement membranes and are generally segregated into four major categories. These include the idiopathic interstitial pneumonias, which are further categorized into seven clinical/radiologic/pathologic subsets. These disorders generally share a common pattern of physiologic abnormality characterized by a restrictive ventilatory defect and reduced diffusing capacity (DLCO). Pulmonary function testing is often used and recommended in their assessment and management. The potential clinical application of physiologic testing includes to aid in diagnosis, although its value in differential diagnosis is limited. Pulmonary function testing also aids in establishing disease severity and in defining prognosis. In nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis, severely decreased DLCO has proven valuable in this regard. Similarly, exertional desaturation to less than 88% at baseline testing and a decrease in FVC (greater than 10%) over the course of short-term follow-up identify patients at particular risk of mortality. Finally, physiologic testing, especially spirometry and DLCO, have demonstrated value in monitoring response to therapy and identifying disease progression.
doi:10.1513/pats.200602-022TK
PMCID: PMC2658684  PMID: 16738195
nonspecific interstitial pneumonia; prognosis; pulmonary function; survival
23.  Future Directions in Idiopathic Pulmonary Fibrosis Research. An NHLBI Workshop Report 
The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.
doi:10.1164/rccm.201306-1141WS
PMCID: PMC3983890  PMID: 24160862
idiopathic pulmonary fibrosis; alveolar epithelial cells; extracellular matrix; interstitial lung disease; inflammation
24.  Randomized Trial of N-acetylcysteine in Idiopathic Pulmonary Fibrosis 
The New England journal of medicine  2014;370(22):2093-2101.
Background
N-acetylcysteine (NAC) has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis (IPF). A placebo-controlled study of this agent administrated orally alone in an IPF population has not been conducted.
Methods
An initially designed three-arm randomized, double-blind, placebo-controlled trial of prednisone plus azathioprine plus NAC (three-drug regimen) versus NAC versus placebo in IPF patients with mild-moderate impairment in pulmonary function was interrupted due to safety concerns associated with the three-drug regimen. The trial continued as a two-arm design (NAC vs. placebo) without other changes and enrolled 133 and 131 patients in the NAC and placebo arms, respectively. The primary outcome measure was the change in forced vital capacity (FVC) over a 60-week period.
Results
Over the 60-week treatment period, there was no difference between the NAC and placebo groups in the decline of FVC (60-week change of −0.18 liters for NAC vs. −0.19 liters for placebo, p=0.77). In addition, there were no significant differences between NAC and placebo for mortality (6 [4.9%] vs. 3 [2.5%] events, p=0.50) or acute exacerbation (3 [2.3%] vs. 3 [2.3%] events, p>0.99).
Conclusions
Compared to placebo NAC offered no benefit for the preservation of FVC in IPF patients with mild-to-moderate physiological abnormalities.
doi:10.1056/NEJMoa1401739
PMCID: PMC4116664  PMID: 24836309
25.  Cell-associated bacteria in the human lung microbiome 
Microbiome  2014;2:28.
Background
Recent studies have revealed that bronchoalveolar lavage (BAL) fluid contains previously unappreciated communities of bacteria. In vitro and in vivo studies have shown that host inflammatory signals prompt bacteria to disperse from cell-associated biofilms and adopt a virulent free-living phenotype. The proportion of the lung microbiota that is cell-associated is unknown.
Results
Forty-six BAL specimens were obtained from lung transplant recipients and divided into two aliquots: ‘whole BAL’ and ‘acellular BAL,’ the latter processed with a low-speed, short-duration centrifugation step. Both aliquots were analyzed via bacterial 16S rRNA gene pyrosequencing. The BAL specimens represented a wide spectrum of lung health, ranging from healthy and asymptomatic to acutely infected. Bacterial signal was detected in 52% of acellular BAL aliquots, fewer than were detected in whole BAL (96%, p ≤ 0.0001). Detection of bacteria in acellular BAL was associated with indices of acute infection [BAL neutrophilia, high total bacterial (16S) DNA, low community diversity, p < 0.01 for all] and, independently, with low relative abundance of specific taxonomic groups (p < 0.05). When whole and acellular aliquots from the same bronchoscopy were directly compared, acellular BAL contained fewer bacterial species (p < 0.05); whole and acellular BAL similarity was positively associated with evidence of infection and negatively associated with relative abundance of several prominent taxa (p < 0.001). Acellular BAL contained decreased relative abundance of Prevotella spp. (p < 0.05) and Pseudomonas fluorescens (p < 0.05).
Conclusions
We present a novel methodological and analytical approach to the localization of lung microbiota and show that prominent members of the lung microbiome are cell-associated, potentially via biofilms, cell adhesion, or intracellularity.
doi:10.1186/2049-2618-2-28
PMCID: PMC4158729  PMID: 25206976
Lung microbiome; Bronchoalveolar lavage; 16S; Pyrosequencing; Pneumonia

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