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1.  Intercellular Adhesion Molecule 1 and Progression of Percent Emphysema: The MESA Lung Study 
Respiratory medicine  2014;109(2):255-264.
Endothelial intercellular adhesion molecule (ICAM) 1 binds neutrophils and facilitates their transmigration into the lung; E-selectin facilitates leukocyte rolling. As neutrophils contribute to tissue destruction in emphysema and chronic obstructive pulmonary disease, we hypothesized that soluble ICAM-1 (sICAM-1) and E-selectin (sE-selectin) would be associated with longitudinal progression of emphysema and lung function decline.
The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45-84 years old without clinical cardiovascular disease in 2000-02. The MESA Lung Study assessed percent emphysema (<-950 Hounsfield units) on cardiac (2000-07) and full-lung CT scans (2010-12), and spirometry was assessed twice over five years. sICAM-1 and sE-selectin were measured at baseline. Mixed-effect models adjusted for demographics, anthropometry, smoking, C-reactive protein, sphingomyelin and scanner factors.
Among 1,865 MESA Lung participants with measurement of sICAM-1 and percent emphysema the mean log-sICAM-1 was 5.5±0.3 ng/mL and percent emphysema increased 0.73 percentage points (95% CI: 0.34, 1.12; P<0.001) over ten years. A one SD increase in sICAM-1 was associated with an accelerated increase in percent emphysema of 0.23 percentage points over ten years (95% CI: 0.06, 0.39; P=0.007). No significant association was found for sE-selectin, or between any adhesion molecule and lung function.
Higher levels of sICAM-1 were independently associated with progression of percent emphysema in a general population sample.
PMCID: PMC4331236  PMID: 25457724
emphysema; CT imaging; endothelium; intercellular adhesion molecule-1
2.  Molecular characteristics of non small cell lung cancer with reduced CHFR expression in The Cancer Genome Atlas (TCGA) project 
Respiratory medicine  2014;109(1):131-136.
CHFR expression has previously been established as a powerful predictor for response to taxane based first-line chemotherapy in non-small cell lung cancer. It is currently unknown however, if reduced CHFR expression correlates with certain molecular subtypes of lung cancer.
In order to determine which patients may benefit from CHFR biomarker testing we conducted the present study to characterize clinical and molecular characteristics of patients with reduced vs. high CHFR expression.
We utilized the extensive molecular and clinical data of the most recent adeno- and squamous cell carcinoma datasets from The Cancer Genome Atlas (TCGA) project. CHFR expression, analyzed by RNAseq, was classified as high vs. low based on the median CHFR expression level and correlated with the presence or absence of lung cancer specific mutations (EGFR, KRAS, ALK, MET, ERBB2, TP53, STK11, ROS1, RET, NF1, Pik3CA for adenocarcinomas and FGFR1, FGFR2, FGFR3, TP53, STK11, EGFR for squamous cell carcinomas).
Reduced CHFR expression was associated with EGFR exon19/21 mutations in adenocarcinoma (OR 0.23 (95%CI: 0.06-0.88) and male gender in squamous cell carcinoma (OR 0.46 (95%CI 0.23-0.92), p=0.02).
PMCID: PMC4277914  PMID: 25477232
3.  Association of pulse wave velocity with total lung capacity: A cross-sectional analysis of the BOLD London study 
Respiratory Medicine  2015;109(12):1569-1575.
Low lung function, measured using spirometry, has been associated with mortality from cardiovascular disease, but whether this is explained by airflow obstruction or restriction is a question that remains unanswered.
To assess the association of total lung capacity (TLC), forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) with several cardio-metabolic and inflammatory markers.
In the follow up of the Burden of Lung Disease (BOLD) study in London, acceptable post-bronchodilator spirometric, pulse rate, pulse wave velocity and blood pressure data were obtained from 108 participants. Blood samples for measurement of cardio-metabolic and inflammatory markers were also collected from these participants. Association of lung function and volume with the different biomarkers was examined in multivariable linear regression models adjusted for potential confounders.
Following adjustment for age, sex, height, and ethnicity, TLC (adjusted coefficient = −1.53; 95% CI: −2.57, −0.49) and FVC (adjusted coefficient = −2.66; 95% CI: −4.98, −0.34) were inversely associated with pulse wave velocity, and further adjustment for smoking status, pack-years and body mass index (BMI) did not materially change these results. FEV1 was inversely associated with systolic blood pressure, and adjustment for smoking status, pack-years and BMI made this association stronger (adjusted coefficient = −9.47; 95% CI: −15.62, −3.32).
The inverse association of pulse wave velocity, which is a marker of cardiovascular disease, with TLC suggests that the association of the former with low FVC is independent of airflow obstruction. The association between FEV1 with systolic blood pressure after adjustment for FVC suggests an association with airflow obstruction rather than with restricted spirometry.
•TLC is inversely associated with pulse wave velocity (i.e. arterial stiffness).•FVC, which is a proxy for TLC, is also inversely associated with pulse wave velocity.•Systolic blood pressure is inversely associated with FEV1.
PMCID: PMC4687496  PMID: 26553156
Lung function; Total lung capacity; Pulmonary restriction; Airflow obstruction; Cardiovascular disease; Pulse wave velocity
4.  Association of Lung Function with Coronary Heart Disease and Cardiovascular Disease Outcomes in Elderly: The Rancho Bernardo Study 
Respiratory medicine  2014;108(12):1779-1785.
Lung function is inversely associated with coronary heart disease (CHD) and cardiovascular disease (CVD). We evaluated the prospective association of reduced lung function by spirometry and CHD or CVD events in older community-dwelling adults.
We studied 1,548 participants (mean age 73.6±9.2 years, 42% males) from the Rancho Bernardo Study using age, sex, and risk-factor adjusted Cox regression to assess pulmonary function (FEV1, FVC, and FEV1/FVC ratio) as a predictor of CHD and CVD events followed for up to 22 years.
Of CVD risk factors, older age, male sex, current/past smoking, physical exercise (<3x a week), and prevalent CVD predicted an increased risk of CHD and CVD. Higher FEV1 and FVC were each associated with a decreased risk of CHD [HR 0.80 (0.73-0.88) for both FEV1 and FVC, per SD, p<.01] and CVD [HR 0.82 (0.74-0.91) for both FEV1 and FVC, per SD, p<.01]. Those in the lowest quartiles of FEV1 and FVC had hazard ratios of 1.68 (1.33-2.13) and 1.55 (1.21-2.00) respectively for CHD and 1.74 (1.34-2.25) and 1.49 (1.13-1.96) respectively for CVD (all p<.01, relative to those in the highest quartile). Similar findings were observed for CHD and CVD mortality. Sex- and age-stratified analyses showed the strongest associations for CHD and CVD events in women and in the oldest participants.
FEV1 and FVC are inversely associated with risk of future CHD and CVD events in older community-dwelling adults and may add to CVD risk stratification in the elderly.
PMCID: PMC4254667  PMID: 25448311
Pulmonary Function Test; Coronary Heart Disease; Cardiovascular Disease; Epidemiology
5.  The role of pulmonary arterial stiffness in COPD 
Respiratory Medicine  2015;109(11):1381-1390.
COPD is the second most common cause of pulmonary hypertension, and is a common complication of severe COPD with significant implications for both quality of life and mortality. However, the use of a rigid diagnostic threshold of a mean pulmonary arterial pressure (mPAP) of ≥25mHg when considering the impact of the pulmonary vasculature on symptoms and disease is misleading. Even minimal exertion causes oxygen desaturation and elevations in mPAP, with right ventricular hypertrophy and dilatation present in patients with mild to moderate COPD with pressures below the threshold for diagnosis of pulmonary hypertension. This has significant implications, with right ventricular dysfunction associated with poorer exercise capability and increased mortality independent of pulmonary function tests.
The compliance of the pulmonary artery (PA) is a key component in decoupling the right ventricle from the pulmonary bed, allowing the right ventricle to work at maximum efficiency and protecting the microcirculation from large pressure gradients. PA stiffness increases with the severity of COPD, and correlates well with the presence of exercise induced pulmonary hypertension. A curvilinear relationship exists between PA distensibility and mPAP and pulmonary vascular resistance (PVR) with marked loss of distensibility before a rapid rise in mPAP and PVR occurs with resultant right ventricular failure. This combination of features suggests PA stiffness as a promising biomarker for early detection of pulmonary vascular disease, and to play a role in right ventricular failure in COPD. Early detection would open this up as a potential therapeutic target before end stage arterial remodelling occurs.
•Pulmonary hypertension is common in COPD.•Right ventricular remodeling occurs at pressures below the diagnostic threshold of PH.•Pulmonary arterial stiffening occurs early in the development of PH.•Non-invasive measurement of pulmonary stiffness may serve as an early biomarker of PH.
PMCID: PMC4646836  PMID: 26095859
Pulmonary disease; Chronic obstructive; Hypertension; Pulmonary; Vascular capacitance; Vascular resistance; Pulmonary heart disease
6.  Efficacy of Mycophenolate Mofetil in Sarcoidosis 
Respiratory medicine  2014;108(11):1663-1669.
Immunosuppressive (IS) therapy is indicated to treat progressive sarcoidosis, but randomized controlled trials to guide physicians in the use of steroid sparing agents are lacking. The aim of this retrospective study was to examine the role of Mycophenolate Mofetil (MMF) as an alternative therapy in the treatment of sarcoidosis.
A retrospective chart review of all patients who had been prescribed MMF between January 2008 and October 2011 was conducted. Patients with insufficient data or who had another IS therapyinitiated concomitantly with MMF, including prednisone, were excluded. Physiological data obtained at the time MMF therapy was initiated as well as six and twelve months before and after therapy was extracted. Longitudinal analyses of the effect of MMF on changes in pulmonary function at MMF start, 6 months, 12 months pre and post MMF therapy were conducted.
37/76 patients met our inclusion/exclusion criteria. There were no statistically significant changes in PFT measurements pre and post MMF therapy. We did find a trend (p=0.07) towards improvement in DLCO 12 months pre and post MMF in patients who were started on MMF due to intolerance to previous IS therapy compared to those who were unresponsive to their previous IS therapy. We also noted a reduction in prednisone dose in those treated with MMF.
MMF appears to offer no extra benefit to sarcoidosis patients unresponsive to previous steroid-sparing agents, but may be beneficial in patients intolerant to their previous steroid-sparing agent. Additional studies investigating the efficacy of MMF as the initial steroid-sparing agent are needed to further clarify the role of MMF in sarcoidosis.
PMCID: PMC4254196  PMID: 25301291
Respiratory medicine  2014;108(11):1688-1695.
The diagnosis of patients with pulmonary infiltrates and human immunodeficiency virus (HIV) infection remains a challenge. In current clinical practice the gold standard for Pneumocystis jirovecii pneumonia (PCP) diagnosis remains the identification of the organism in broncoalveolar lavage (BAL) using microscopy (e.g., silver stain). (1->3)-β -D-glucan (BG) is a polysaccharide that is present within the cell wall of Pneumocystis and other fungi. We analyzed serum and BAL lavage fluid from a cohort of 119 patients that did have HIV, a diagnosis of pneumonia and underwent bronchoscopy (FOB) for diagnosis of PCP. The discriminative power of serum BG for the diagnosis of PCP in this group of patients was very high. Using a cutoff of 300 pg/mL, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 91%, 92%, 89% and 93% respectively. A model for ROC with just serum BG (N = 108) had an AUC of 0.95. Serum procalcitonin (PCT) and BAL BG were not as accurate for the diagnosis of PCP. For BAL BG using a cutoff of 783 pg/mL, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 72%, 79%, 72% and 79% respectively. The differences between the medians for serum PCT between the group with a without PCP did not reach statistical significance (p=0.6137). The measurement of serum BG should be incorporated in the diagnostic work up of HIV positive patients with dyspnea and infiltrates on chest X ray. Our study confirms the diagnostic value of serum BG previously reported by others but we add a cutoff value that we believe is more accurate for patients with AIDS and suspicion of PCP.
PMCID: PMC4297544  PMID: 25448310
Respiratory medicine  2014;108(10):1469-1480.
Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1).
Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD1 and smoking control subjects.
K-means clustering of GOLD 1 subjects identified putative “near-normal”, “airway-predominant”, “emphysema-predominant” and “lowest FEV1 % predicted” subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1 % predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects.
Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity.
PMCID: PMC4253548  PMID: 25154699
pulmonary disease; chronic obstructive; population characteristics; cluster analysis; genetic association
9.  Reduced dynamic hyperinflation after LVRS is associated with improved exercise tolerance 
Respiratory medicine  2014;108(10):1491-1497.
Dynamic hyperinflation (DH) after lung volume reduction surgery (LVRS) has not been well studied. It is not known if reductions in DH correlate with improvements in exercise performance post-LVRS.
Forty-two upper-lobe predominant emphysema patients who underwent LVRS were analyzed. Inspiratory capacity was measured every 2 minutes during symptom-limited cardiopulmonary exercise test (CPET) and end-expiratory lung volumes (EELV) were calculated. The main measure of DH was EELV/TLC ratio matched at metabolic isotimes (based on the post-rehabilitation VCO2max).
Patients had very severe airflow obstruction (FEV1 28.3±7.0% predicted), were hyperinflated (TLC 125±17% predicted) and gas trapped (RV 198±39% predicted). Compared to the post-rehab baseline, dynamic hyperinflation (EELV/TLC) was significantly reduced after LVRS at 6, 12, 24, and 36 months. There were also increases in inspiratory reserve volume at matched isotimes after surgery. Patients adopted a slower, deeper breathing pattern during exercise after LVRS, which strongly correlated to reductions in DH. There were significant correlations between reductions in DH (EELV/TLC @50%VCO2max) and improvements in 6 minute walk distance (Pearson r= -0.411, p=0.02, n=33) and maximal watts on CPET (Spearman r=-0.536, p=0.001, n=33) when comparing post-rehabilitation and 6 month post-LVRS values.
Dynamic hyperinflation during exercise was reduced after LVRS (up to 3 years) and there was a strong association between alterations in breathing pattern and reduced DH after LVRS. This is the first study to demonstrate that reductions in DH correlated with improved exercise performance following LVRS.
PMCID: PMC4505940  PMID: 25135742
Respiratory medicine  2014;108(8):1141-1152.
Aerobic exercise training is a recognized approach for improving functional capacity in COPD. People with greater disease severity often have difficulty achieving higher aerobic exercise training intensity. The effects of resistance training prior to aerobic training were examined to determine if this sequential approach was associated with greater gains in functional status than aerobic training alone or concurrent aerobic and resistance training.
Patients were randomized to: 1) sequential resistance then aerobic training (RT-then-AT) (8 weeks resistance training followed by 8 weeks aerobic exercise training), 2) control group (CE-then-AT+RT) (8 weeks of ‘sham’ training followed by 8 weeks concurrent aerobic and resistance training), 3) control group (CE-then-AT) (8 weeks ‘sham’ training followed by 8 weeks aerobic training). Outcomes were assessed at study entry, after week 8, and after week 16: aerobic exercise performance; muscle strength and endurance.
75 patients completed training: FEV1 %pred 40±10, V̇O2peak %predicted, 71±22, fat-free mass index 19.5±3.1. RT-then-AT had greater acquisition of peripheral muscle endurance than CE-then-AT+RT and CE-then-AT, but improvements in aerobic exercise performance were similar. Improvements in muscle strength were similar between RT-then-AT and CE-then-AT+RT. Sarcopenia was associated with poorer attendance, and lower aerobic and resistance training volumes.
Although the sequential approach to resistance and aerobic training yielded a greater increase in muscle endurance and higher resistance training volume compared to concurrent resistance and aerobic training, other training outcomes were similar between the two groups, thus the sequential approach is not clearly superior to the concurrent approach in severe COPD. Identifier NCT01058213.
PMCID: PMC4130772  PMID: 24958605
dyspnea; leg fatigue; muscle strength; pulmonary rehabilitation; COPD
11.  Obesity and symptoms of depression contribute independently to the poor asthma control of obesity 
Respiratory medicine  2014;108(8):1100-1107.
Obesity is a major risk factor for poorly controlled asthma, but the reasons for poor asthma control in this patient population are unclear. Symptoms of depression have been associated with poor asthma control, and increase with higher body mass index (BMI). The purpose of this study was to assess whether depressive symptoms underlie poor asthma control in obesity.
We determined the relationship between BMI, psychological morbidity and asthma control at baseline in a well-characterized patient population participating in a clinical trial conducted by the American Lung Association-Asthma Clinical Research Centers.
Obese asthmatic participants had increased symptoms of depression (Center for Epidemiologic Studies Depression Scale score in lean 10·1±8·1, overweight 10·0±8·1, obese 12·4±9·9; p=0·03), worse asthma control (Juniper Asthma Control Questionnaire score in lean 1·43±0·68, overweight 1·52±0·71, obese 1·76±0·75; p<0·0001), and worse asthma quality of life (scores in lean 5·21±1·08, overweight 5·08±1·05, obese 4·64±1·09; p<0·0001). Asthmatics with obesity and those with symptoms of depression both had a higher risk of having poorly controlled asthma (adjusted odds ratio of 1·83 CI 1·23-3·52 for obesity, and 2·08 CI 1·23-3·52 for depression), but there was no interaction between the two.
Obesity and symptoms of depression are independently associated with poor asthma control. As depression is increased in obese asthmatics it may be an important co-morbidity contributing to poor asthma control in this population, but factors other than depression also contribute to poor asthma control in obesity.
PMCID: PMC4130899  PMID: 24947900
obesity; asthma; depression
12.  Age at asthma onset and subsequent asthma outcomes among adults with active asthma 
Respiratory medicine  2013;107(12):1829-1836.
Little is known about the extent to which the age at which asthma first began influences respiratory health later in life. We conducted these analyses to examine the relationship between age at asthma onset and subsequent asthma-related outcomes.
We used data from 12,216 adults with asthma who participated in the 2010 Behavioral Risk Factor Surveillance System Asthma Call-back Survey to describe the distribution of age at asthma onset. Linear regression was used to estimate associations of age at asthma onset with asthma-related outcomes, including symptoms in the past 30 days and asthma-related emergency visits.
Asthma onset before age 16 was reported by an estimated 42% of adults with active asthma, including 14% with onset at 5–9 years of age who reported experiencing any asthma symptoms on 21% of days in the past month. Compared to this group, the percentage of days in the past month with any asthma symptoms was 14.8% higher (95% confidence interval (CI): 5.4, 24.1) among those whose asthma onset occurred at <1 year. When age at onset occurred at 10 years or older there was little change in the prevalence of asthma-related emergency visits across age at onset categories.
Age at asthma onset may affect subsequent asthma-related outcomes.
PMCID: PMC4512733  PMID: 24139624
Asthma; Epidemiology; Prevalence; Respiratory health; Surveillance
13.  Depressed Mood Predicts Pulmonary Rehabilitation Completion among Women, but not Men 
Respiratory medicine  2014;108(7):1007-1013.
As many as 30% of patients who start pulmonary rehabilitation (PR) fail to complete it, and depressed mood has been associated with PR non-completion. Depression is more common in women than men with COPD and historically women with COPD have been under studied. However, no studies to date have investigated gender-specific predictors of PR completion.
The study included 111 patients with COPD who enrolled in a community based outpatient PR program in Providence, RI. Patients who attended 20 or more sessions were designated “completers.” Depression was measured using the CES-D. Logistic regression models were evaluated to test depressed mood as a predictor of PR completion. Analyses controlled for demographic and health variables found to differ between completers and non-completers.
Patients were 95% white and 49.5% women, and 74% had a GOLD stage ≥ 3. Sixty-eight percent of patients were PR completers. A logistic regression model, showed that lower depressed mood independently predicted PR completion across all patients (adjusted OR = 0.92, p = .002). In gender-stratified analyses, lower depressed mood was an independent predictor of PR completion for women (adjusted OR = 0.91, p = .024) but not men (adjusted OR = 0.97, p = .45). Greater six-minute walk test distance was also an independent predictor of PR completion among women.
Depressed mood is an important predictor of completion of community based PR among women. Screening and brief treatment of depression should be considered in practice.
PMCID: PMC4116192  PMID: 24820243
14.  The effect of corticosteroids on quality of life in a sarcoidosis clinic: The results of a propensity analysis 
Respiratory medicine  2015;109(4):526-531.
Both sarcoidosis and its treatment may worsen health related quality of life (HRQoL). We performed a propensity analysis of sarcoidosis-specific HRQoL patient reported outcome measures (PRO) to disentangle the effects of sarcoidosis and corticosteroid therapy on HRQoL in sarcoidosis outpatients.
Consecutive outpatient sarcoidosis patients were administered modules from two sarcoidosis-specific HRQoL PROs: the Sarcoidosis Health Questionnaire (SHQ) and the Sarcoidosis Assessment Tool (SAT). Patients were divided into those that received ≤500 mg of prednisone (PRED-LOW) versus >500 mg of prednisone (PRED-HIGH) over the previous year. SAT and SHQ scores were initially compared in the two corticosteroid groups. Then a multivariate analysis was performed using a propensity score analysis adjusted for race, age, gender and the severity of illness.
In the unadjusted analysis, the PRED-HIGH group demonstrated the following worse HRQoL scores compared to the LOW-PRED group: SHQ Daily (p = 0.02), SAT satisfaction (p = 0.03), SAT daily activities (p = 0.03). In the propensity analysis, the following domains demonstrated worse HRQoL in the PRED-HIGH group than the PRED-LOW group: SAT fatigue (p < 0.0001), SAT daily activities (p = 0.03), SAT satisfaction (p = 0.03). All these differences exceeded the established minimum important difference for these SAT domains. The SHQ Physical score appeared to demonstrate a borderline improved HRQoL in the PRED-HIGH versus the PRED-LOW group (p = 0.05).). In a post-hoc exploratory analysis, the presence of cardiac sarcoidosis may have explained the quality of life differences between the two corticosteroid groups.
Our cohort of sarcoidosis clinic patients who received ≤500 mg of prednisone in the previous year had an improved HRQoL compared to patients receiving >500 mg on the basis of two sarcoidosis-specific PROs after adjusting for severity of illness. These data support the need to measure HRQoL in sarcoidosis trials, and suggest that the search should continue for effective alternative medications to corticosteroids.
PMCID: PMC4447298  PMID: 25698652
Sarcoidosis; Quality of life; Corticosteroids; Patient reported outcomes
15.  Predictors for clinical trial participation in the rare lung disease lymphangioleiomyomatosis☆ 
Respiratory medicine  2009;104(4):578-583.
Lymphangioleiomyomatosis (LAM) is a rare, progressive and frequently lethal cystic lung disease that almost exclusively affects women and has no proven therapies. An improved understanding of the pathogenesis has identified promising molecular targets for clinical trials. Although barriers, modifiers, and benefits for clinical trial participation in common diseases such as cancer have been studied, we are unaware of such evaluations concerning rare diseases.
We performed a survey of a population-based registry of 780 LAM subjects in North America to identify predictors of trial participation. Logistic regression analysis evaluated the association of demographic and clinical features with trial participation.
41 of 263 (16%) LAM patient respondents in North America had participated in a clinical trial. Age, disease duration, lack of any college education, use of oxygen therapy, and presentation without chest pain were associated with trial participation in unadjusted analyses. Multivariate analyses indicate that patient age was the strongest independent predictor for trial participation (OR = 2.07, p = 0.004 per decade greater of patient age). Common reasons reported against trial participation included not meeting enrollment criteria (44%), drug toxicity (25%), and stable disease (20%). The most frequent reason reported for trial participation was to help future patients (85%).
Study entry criteria, drug toxicity, and stability of disease are barriers to trial enrollment among subjects with LAM. Older LAM patients and those with more advanced disease are more likely to have participated in clinical trials. Altruism is commonly a motivating factor.
PMCID: PMC4407662  PMID: 19962873
Lymphangioleiomyomatosis; Clinical trial; Survey; Rare diseases; Trial participation
Respiratory medicine  2013;108(3):491-499.
As the clinical significance of chronic bronchitis among smokers without airflow obstruction is unclear, we sought to determine morbidity associated with this disorder.
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.
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.
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.
PMCID: PMC3943716  PMID: 24280543
Cough; quality of life; gastroesophageal reflux; occupational exposure; GERD; tobacco
18.  [No title available] 
PMCID: PMC4065171  PMID: 24411842
19.  Annual rates of change in pre- vs. post- bronchodilator FEV1 and FVC over 4 years in moderate to very severe COPD 
Respiratory medicine  2013;107(12):1904-1911.
While the slope of decline in FEV1 has traditionally been calculated from the post- rather than the pre-bronchodilator measurement in COPD interventional trials, it is not clear whether and to what extent these two slopes differ in symptomatic patients with COPD. Therefore, we used data from the 4-year UPLIFT trial of tiotropium 18 mcg QD vs. placebo to compare annual rates of change in pre- vs. post-bronchodilator FEV1 in 5041 patients with moderate to very severe COPD (mean FEV1 48% pred) in whom the post-bronchodilator FEV1 was measured after 4 inhalations of two different classes of short-acting inhaled bronchodilators at baseline and 1 month and every 6 months post-randomization over 4 years. Linear mixed effects models were used to estimate annual rates of decline in FEV1 and FVC pre- and post- bronchodilator in each treatment group separately, after adjusting for height, gender, smoking status, baseline % predicted FEV1 or FVC, and baseline acute % improvement in lung function. The slopes of the post-bronchodilator FEV1 and FVC were significantly steeper than the pre-bronchodilator slopes regardless of treatment arm (p < 0.001), while the estimated variances of the slopes were similar. Post-bronchodilator increases in FEV1 and FVC diminished progressively and significantly (p < 0.0001) over the 4-year trial, suggesting a possible explanation for the significant differences between the pre- and post-bronchodilator slopes. While the reasons for these differences are not completely clear, they are important to consider when assessing treatment effects on rates of decline in FEV1 and FVC.
PMCID: PMC4284059  PMID: 23972968
slope of FEV1 decline; post-bronchodilator; COPD; UPLIFT
Respiratory medicine  2013;108(1):162-170.
Firefighters exposed to World Trade Center (WTC) dust have developed chronic rhinosinusitis (CRS) and abnormal forced expiratory volume in 1 second (FEV1). Overlapping but distinct immune responses may be responsible for the clinical manifestations of upper and lower airway injury. We investigated whether a panel of inflammatory cytokines, either associated or not associated with WTC-LI, can predict future chronic rhinosinusitis disease and its severity.
Serum obtained within six months of 9/11/2001 from 179 WTC exposed firefighters presenting for subspecialty evaluation prior to 3/2008 was assayed for 39 cytokines. The main outcomes were medically managed CRS (N=62) and more severe CRS cases requiring sinus surgery (N=14). We tested biomarker-CRS severity association using ordinal logistic regression analysis.
Increasing serum IL-6, IL-8, GRO and neutrophil concentration reduced the risk of CRS progression. Conversely, increasing TNF-α increased the risk of progression. In a multivariable model adjusted for exposure intensity, increasing IL-6, TNF-α and neutrophil concentration remained significant predictors of progression. Elevated IL-6 levels and neutrophil counts also reduced the risk of abnormal FEV1 but in contrast to CRS, increased TNF-α did not increase the risk of abnormal FEV1.
Our study demonstrates both independent and overlapping biomarker associations with upper and lower respiratory injury, and suggests that the innate immune response may play a protective role against CRS and abnormal lung function in those with WTC exposure.
PMCID: PMC3946892  PMID: 24290899
one airway; chronic rhinosinusitis; World Trade Center; innate immunity
22.  The relation of circulating YKL-40 to levels and decline of lung function in adult life 
Respiratory medicine  2013;107(12):10.1016/j.rmed.2013.07.013.
YKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers.
To determine the longitudinal relation of circulating YKL-40 to levels and lung function decline in the general population.
We used longitudinal data from up to 12 surveys from the population-based TESAOD study which was conducted in Tucson, Arizona between 1972-1996. In cross-sectional analyses, we also used data from 3 Spanish centers of the multicenter ECRHS study (ECRHS-Sp). Serum YKL-40 was measured at baseline in TESAOD and in survey 2 in ECRHS-Sp using ELISAs. Multivariate linear regression was used to test associations of serum YKL-40 to concomitant lung function. In TESAOD, random coefficients models were used to test associations of serum YKL-40 to subsequent decline of lung function.
Data on YKL-40 and lung function were available from 1088 TESAOD and 854 ECRHS-Sp adult participants (59% and 51% females; respectively). In adjusted multivariate meta-analyses, being in the highest YKL-40 quartile was associated cross-sectionally with significant deficits in FEV1 and FVC %predicted. In adjusted longitudinal analyses, TESAOD participants in the top YKL-40 quartile had an FEV1 decline that was 5 ml/yr (p=0.05) faster than subjects in the third quartile, 5 ml/yr (p=0.02) faster than subjects in the second quartile, and 10 ml/yr (p<0.001) faster than subjects in the lowest YKL-40 quartile. These longitudinal effects were particularly strong in smokers and absent in never smokers. After adjusting for covariates, as compared with the other three quartiles combined the top YKL-40 quartile was associated with a 9 ml/yr (p=0.001) faster FEV1 decline among smokers, while no significant effects were found among never smokers (2 ml/yr, p=0.35).
Circulating YKL-40 is associated with levels and decline of lung function in the general population and may be a biomarker of susceptibility to the long-term effects of cigarette smoking.
PMCID: PMC3864627  PMID: 23920328
YKL-40; lung function; smoking
23.  HIV and asthma, is there an association? 
Respiratory medicine  2012;106(4):493-499.
To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection.
We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data.
HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported.
The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART.
PMCID: PMC4235227  PMID: 22285768
Asthma; Airway hyper-responsiveness; HIV; Antiretroviral
24.  Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning 
Respiratory medicine  2013;107(11):10.1016/j.rmed.2013.08.018.
Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.
PMCID: PMC3848251  PMID: 24055406
EGFR; KRAS; lung cancer; never smoking; China; driver mutations; tumor tissue
Respiratory medicine  2013;107(10):1547-1557.
Chronic Obstructive Pulmonary Disease (COPD) is a common disorder of Veterans that causes significant morbidity and mortality. To measure Veterans’ perceptions about COPD, the effect of COPD on their lives and health, and their needs for improved health, we performed a postal survey.
3263 Veterans with a diagnosis of COPD who received care at the Cincinnati Veterans Affairs Medical Center in 2008 were stratified into quintiles by Veterans Health Administration - associated COPD healthcare cost and uniformly sampled.
493 of 1000 surveys (49%) were completed and returned. COPD had different effects on respondents in top and bottom quintiles (highest and lowest COPD-related cost) for: knowledge of COPD diagnosis (89% vs 73%, p=0.03); activities affected by breathing, including work (69% vs 45%), recreation (85% vs 62%), change in living arrangements (36% vs 16%), and increased need for help (54% vs 25%) (p<0.05 for all comparisons); emotional effect of respiratory symptoms, including depression (53% vs 30%), fear (41% vs 15%), and helplessness (49% vs 24%) (p<0.05 for all comparisons). 91% of Veterans were prescribed inhalers and one quarter had difficulties using them. 25% of Veterans did nothing when they had symptoms of an exacerbation.
COPD has profound effects on Veterans’ breathing related activities and generates many negative emotions. Primary care providers are critical in conveying the diagnosis of COPD and providing information about the disease and its management. Veterans with COPD adhere poorly to their medications, and report little instruction about COPD or its management.
PMCID: PMC3783603  PMID: 23827725

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