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1.  [No title available] 
PMCID: PMC4065171  PMID: 24411842
2.  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.
doi:10.1016/j.rmed.2013.08.001
PMCID: PMC4284059  PMID: 23972968
slope of FEV1 decline; post-bronchodilator; COPD; UPLIFT
3.  ONE AIRWAY: BIOMARKERS OF PROTECTION FROM UPPER AND LOWER AIRWAY INJURY AFTER WORLD TRADE CENTER EXPOSURE 
Respiratory medicine  2013;108(1):162-170.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.rmed.2013.11.002
PMCID: PMC3946892  PMID: 24290899
one airway; chronic rhinosinusitis; World Trade Center; innate immunity
5.  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.
Background
YKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers.
Aim
To determine the longitudinal relation of circulating YKL-40 to levels and lung function decline in the general population.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.rmed.2013.07.013
PMCID: PMC3864627  PMID: 23920328
YKL-40; lung function; smoking
6.  HIV and asthma, is there an association? 
Respiratory medicine  2012;106(4):493-499.
Summary
Objective
To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.rmed.2011.12.017
PMCID: PMC4235227  PMID: 22285768
Asthma; Airway hyper-responsiveness; HIV; Antiretroviral
7.  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.
doi:10.1016/j.rmed.2013.08.018
PMCID: PMC3848251  PMID: 24055406
EGFR; KRAS; lung cancer; never smoking; China; driver mutations; tumor tissue
8.  THERAPEUTIC PARALYSIS IN VETERANS WITH COPD 
Respiratory medicine  2013;107(10):1547-1557.
Summary
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.rmed.2013.05.013
PMCID: PMC3783603  PMID: 23827725
9.  SEX DIFFERENCES IN ASTHMA SYMPTOM 1 PROFILES AND CONTROL IN THE AMERICAN LUNG ASSOCIATION ASTHMA CLINICAL RESEARCH CENTERS 
Respiratory medicine  2013;107(10):10.1016/j.rmed.2013.07.024.
Objective
Important differences between men and women with asthma have been demonstrated, with women describing more symptoms and worse asthma-related quality of life (QOL) despite having similar or better pulmonary function. While current guidelines focus heavily on assessing asthma control, they lack information about whether sex-specific approaches to asthma assessment should be considered. We sought to determine if sex differences in asthma control or symptom profiles exist in the well-characterized population of participants in the American Lung Association Asthma Clinical Research Centers (ALA-ACRC) trials.
Methods
We reviewed baseline data from four trials published by the ALA-ACRC to evaluate individual item responses to three standardized asthma questionnaires: the Juniper Asthma Control Questionnaire (ACQ), the multi-attribute Asthma Symptom Utility Index (ASUI), and Juniper Mini Asthma Quality of Life Questionnaire (mini-AQLQ).
Results
In the poorly-controlled population, women reported similar overall asthma control (mean ACQ 1.9 vs. 1.8; p=0.54), but were more likely to report specific symptoms such as nocturnal awakenings, activity limitations, and shortness of breath on individual item responses. Women reported worse asthma-related QOL on the mini-AQLQ (mean 4.5 vs. 4.9; p<0.001) and more asthma-related symptoms with a lower mean score on the ASUI (0.73 vs. 0.77; p=<0.0001) and were more likely to report feeling bothered by particular symptoms such as coughing, or environmental triggers.
Conclusions
In participants with poorly-controlled asthma, women had outwardly similar asthma control, but had unique symptom profiles on detailed item analyses which were evident on evaluation of three standardized asthma questionnaires.
doi:10.1016/j.rmed.2013.07.024
PMCID: PMC3816372  PMID: 23972381
10.  Nitrogen Dioxide and Allergic Sensitization in the 2005–2006 National Health and Nutrition Examination Survey 
Respiratory medicine  2013;107(11):1763-1772.
Background
Allergic sensitization is a risk factor for asthma and allergic diseases. The relationship between ambient air pollution and allergic sensitization is unclear.
Objective
To investigate the relationship between ambient air pollution and allergic sensitization in a nationally representative sample of the US population.
Methods
We linked annual average concentrations of nitrogen dioxide (NO2), particulate matter ≤ 10 µm (PM10), particulate matter ≤ 2.5 µm (PM25), and summer concentrations of ozone (O3), to allergen-specific immunoglobulin E (IgE) data for participants in the 2005–2006 National Health and Nutrition Examination Survey (NHANES). In addition to the monitor-based air pollution estimates, we used the Community Multiscale Air Quality (CMAQ) model to increase the representation of rural participants in our sample. Logistic regression with population-based sampling weights was used to calculate adjusted prevalence odds ratios per 10 ppb increase in O3 and NO2, per 10 µg/m3 increase in PM10, and per 5 µg/m3 increase in PM2.5 adjusting for race, gender, age, socioeconomic status, smoking, and urban/rural status.
Results
Using CMAQ data, increased levels of NO2 were associated with positive IgE to any (OR 1.15, 95% CI 1.04, 1.27), inhalant (OR 1.17, 95% CI 1.02, 1.33), and outdoor (OR 1.16, 95% CI 1.03, 1.31) allergens. Higher PM2.5 levels were associated with positivity to indoor allergen-specific IgE (OR 1.24, 95% CI 1.13, 1.36). Effect estimates were similar using monitored data.
Conclusions
Increased ambient NO2 was consistently associated with increased prevalence of allergic sensitization.
doi:10.1016/j.rmed.2013.08.010
PMCID: PMC4071349  PMID: 24045117
air pollution; allergic; sensitization; epidemiology; NHANES; IgE
11.  Asthma in the elderly: The role of exhaled nitric oxide measurements 
Respiratory medicine  2013;107(5):785-787.
Summary
Asthma in the elderly is poorly understood because only a small minority of asthma studies have investigated this patients group. Fractional Exhaled Nitric Oxide (FENO) has been extensively studied in children and adults with asthma, but little is known about FENO in elderly asthmatics. We studied the role of serial measurements of FENO in elderly subjects with asthma.
Thirty stable asthmatics 65 years old and older were followed for one year with evaluations at baseline and every three months. We looked for associations between FENO and subjects’ demographics, comorbidities, asthma treatment, spirometric values and Asthma Control Test (ACT) scores. FENO was not elevated in our study subjects throughout the study period (mean < 30 ppb). FENO significantly increased and FEV1% decreased between first and last study visit, while ACT scores and steroid dose remained unchanged. No significant correlation was found between FENO and FEV1/FVC, other spirometric values, inhaled steroid dose or ACTscores at any time point. No associations of FENO were found with age, sex, Body Mass Index (BMI), atopic status, disease duration, presence of rhinitis or gastroesophageal reflux disease (GERD), or other medications used. Moderate asthma exacerbations did not consistently cause an increase of FENO.
In stable elderly asthmatic patients, FENO was not elevated and did not correlate with subjects’ demographics, comorbidities, treatment, symptoms or spirometric values. Routine measurements of FENO may not be clinically valuable in elderly asthmatics.
doi:10.1016/j.rmed.2013.01.018
PMCID: PMC4034737  PMID: 23481173
Asthma; FENO; Elderly
12.  Defective efferocytosis by alveolar macrophages in IPF patients 
Respiratory medicine  2012;106(12):1800-1803.
Summary
Rationale
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia. The pathogenicity of IPF has been widely investigated but still remains to be clarified. Efferocytosis, the specialized recognition and ingestion of apoptotic cells by phagocytes, is essential for the resolution of inflammation in the lungs and repair of injured tissues. Impaired efferocytosis contributes to the pathogenesis of chronic lung diseases such as emphysema and cystic fibrosis. We hypothesized that efferocytosis would also be reduced in alveolar macrophages isolated from subjects with IPF.
Methods
Efferocytosis, was evaluated using Wright-Giemsa stained cell preparations isolated from the bronchoalveolar lavage (BAL) fluid of patients with IPF (n = 5), nonspecific interstitial pneumonitis (n = 6), cryptogenic organizing pneumonia (n = 4) and eosinophilic pneumonia (EP) (n = 5).
Results
Uningested apoptotic cells were significantly higher in BAL fluid from patients with IPF compared to other forms of interstitial lung disease. Macrophages isolated from patients with eosinophilic pneumonia had significantly fewer phagocytic ingestions than macrophages from the other three groups.
Conclusion
Efferocytosis by alveolar macrophages was significantly lower in subjects with IPF compared to subjects with other interstitial pneumonia. Dysregulated efferocytosis may contribute to the pathogenesis of IPF.
doi:10.1016/j.rmed.2012.08.020
PMCID: PMC4030720  PMID: 22999220
Idiopathic pulmonary fibrosis; Efferocytosis; BAL; Idiopathic interstitial pneumonia
13.  Complement components as potential therapeutic targets for asthma treatment 
Respiratory medicine  2014;108(4):543-549.
Summary
Asthma is the most common respiratory disorder, and is characterized by distal airway inflammation and hyperresponsiveness. This disease challenges human health because of its increasing prevalence, severity, morbidity, and the lack of a proper and complete cure. Asthma is characterized by TH2–skewed inflammation with elevated pulmonary levels of IL-4, IL-5, and IL-13 levels. Although there are early forays into targeting TH2 immunity, less-specific corticosteroid therapy remains the immunomodulator of choice. Innate immune injury mediated by complement components also act as potent mediators of the allergic inflammatory responses and offer a new and exciting possibility for asthma immunotherapy. The complement cascade consists of a number of plasma- and membrane-bound proteins, and the cleavage products of these proteins (C3 and C5) regulate the magnitude of adaptive immune responses. Complement protein are responsible for many pathophysiological features of asthma, including inflammatory cell infiltration, mucus secretion, increases in vascular permeability, and smooth muscle cell contraction. This review highlights the complement-mediated injury during asthma inflammation, and how blockade of active complement mediators may have therapeutic application.
doi:10.1016/j.rmed.2014.01.005
PMCID: PMC4011641  PMID: 24468195
Complement mediated injury; Asthma; Anaphylatoxins
14.  Effect of aerobic exercise training on fatigue and physical activity in patients with pulmonary arterial hypertension 
Respiratory medicine  2013;107(5):778-784.
Summary
Objective
To investigate the effectiveness of an exercise intervention for decreasing fatigue severity and increasing physical activity in individuals with pulmonary arterial hypertension (PAH). A small, phase 2 randomized clinical trial of the effect of aerobic exercise training on fatigue severity and physical activity in patients with idiopathic or PAH associated with other conditions was conducted.
Methods
Twenty-four patients with PAH (24 female; age: 54.4 ± 10.4 years; BMI: 30.8 ± 7.2 kg/m2) participated in the study. A convenience sample was recruited in which 9% (28 of 303) of screened patients were enrolled. The project was carried out in a clinical pulmonary rehabilitation clinic during existing pulmonary rehabilitation program sessions.
Patients with PH were randomized into a 10-week program that consisted of patient education only or patient education plus an aerobic exercise-training regimen. Both groups received 20 lectures, two per week over the 10-weeks, on topics related to PAH and its management. The aerobic exercise training consisted of 24–30 sessions of treadmill walking for 30–45 min per session at an intensity of 70–80% of heart rate reserve, three days per week over the 10 weeks.
Results
After 10-weeks of intervention, patients receiving aerobic exercise training plus education reported routinely engaging in higher levels of physical activity (p < 0.05) and a decrease in fatigue severity (p = 0.03). Patients in the education only group did not report changes in fatigue severity or participation in physical activity.
Conclusions
The 10-week aerobic exercise training intervention resulted in increased physical activity and decreased fatigue in individuals with PAH.
doi:10.1016/j.rmed.2013.02.006
PMCID: PMC3752591  PMID: 23478192
Hypertension; Pulmonary; Fatigue; Motor activity; Exercise
15.  Sulforaphane induces SLPI secretion in the nasal mucosa 
Respiratory medicine  2012;107(3):472-475.
Summary
Cells lining the respiratory tract are equipped with mechanisms that dampen the effects of oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a mediator involved in regulating oxidative stress. Recent data indicate Nrf2 also controls expression of secretory leukocyte protease inhibitor (SLPI). Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, enhances Nrf2 activity. Therefore, we hypothesized that SFN supplementation induces SLPI secretion in the nasal mucosa in an Nrf2 dependent manner. Healthy nonsmoking adults ingested SFN-containing broccoli shake homogenate (BSH) for 3 consecutive days. Nasal lavage fluid (NLF) was collected before and after BSH ingestion and analyzed for SLPI protein levels. In follow up in vitro experiments, differentiated primary nasal epithelial cells were used to evaluate the relationship between SFN, Nrf2, and SLPI. Epithelial cells were transduced with Nrf2-specific shRNA to examine the regulatory role of Nrf2 on SLPI expression. Supplementation with BSH significantly increased SLPI levels in NLF. SFN supplementation in vitro significantly enhanced SLPI secretion and these effects were significantly decreased in cells transduced with Nrf2-specific shRNA.
doi:10.1016/j.rmed.2012.11.006
PMCID: PMC3640824  PMID: 23195333
SLPI; Sulforaphane; Nasal mucosa
16.  PREVALENCE AND CLINICAL SIGNIFICANCE OF CIRCULATING AUTOANTIBODIES IN IDIOPATHIC PULMONARY FIBROSIS 
Respiratory medicine  2012;107(2):249-255.
doi:10.1016/j.rmed.2012.10.018
PMCID: PMC3543473  PMID: 23186614
idiopathic pulmonary fibrosis; autoantibodies; anti-nuclear antibody; rheumatoid factor
18.  Increases in airway eosinophilia and a th1 cytokine during the chronic asymptomatic phase of asthma 
Respiratory medicine  2010;104(10):1436-1443.
Summary
Background
Studies using allergen challenge models have suggested Th2 cytokines promote airway inflammation in asthma. We assessed mediators of airway inflammation during the chronic asymptomatic phase of asthma.
Methods
Nine non-atopic asthma (NAA) patients, 19 atopic asthma (AA) patients, 20 atopic controls (AC), and 38 normal controls (NC) underwent sputum induction while asymptomatic. Sputum total cell counts and differentials were determined; levels of cytokines IL-4, IL-5, IL-13, GM-CSF, and IFN-γ, and chemokines eotaxin (CCL11) and RANTES (CCL5) were measured by ELISA; and levels of eosinophil-derived neurotoxin (EDN) were measured by radioimmunoassay.
Results
NAA patients showed higher % eosinophils and total eosinophils compared to AA. NAA and AA patients showed higher IFN-γ and EDN levels compared to AC and NC, with no differences in IL-4, IL-5, or IL-13 levels among the four groups. GM-CSF levels were higher in AA patients compared to AC or NC. In NAA, AA, and AC patients, % eosinophils and EDN levels correlated positively with IFN-γ, GM-CSF, eotaxin, and RANTES, but not with IL-5 levels.
Conclusions
Baseline airway inflammation of intrinsic and extrinsic asthma is characterized by eosinophilic inflammation and the Th1 cytokine, IFN-γ. GM-CSF, instead of IL-5, and chemokines may coordinate airway eosinophilia during the chronic asymptomatic phase of asthma.
doi:10.1016/j.rmed.2010.03.023
PMCID: PMC3899099  PMID: 20709516
Eosinophil; Cytokine; Intrinsic asthma
19.  Lymphocyte subsets in experimental rhinovirus infection in chronic obstructive pulmonary disease☆ 
Respiratory Medicine  2014;108(1):78-85.
Summary
Background
COPD is associated with increased numbers of T cells in the lungs, particularly CD8+ T cells. The mechanisms of increased T cells are unknown but may be related to repeated virus infections in COPD patients. We analysed lymphocyte subsets in blood and bronchoalveolar lavage in smokers and COPD subjects during experimental rhinovirus infections.
Methods
Lymphocytes were isolated from blood and bronchoalveolar lavage from COPD subjects and non-obstructed smokers prior to, and following experimental rhinovirus infection. Lymphocyte surface markers and intracellular cytokines were analysed using flow cytometry.
Results
Following rhinovirus infection CD4+ and CD8+ T cell numbers in the COPD subjects were significantly reduced in blood and CD3+ and CD8+ T cells increased in bronchoalveolar lavage compared to baseline. T cells did not increase in BAL in the control subjects. CD3+ T cells correlated with virus load.
Conclusions
Following rhinovirus infection T cells move from the circulation to the lung. Repeated virus infections may contribute to T cell accumulation in COPD patients.
doi:10.1016/j.rmed.2013.09.010
PMCID: PMC3969590  PMID: 24099891
Chronic obstructive pulmonary disease; Acute exacerbations of COPD; Respiratory viruses; T lymphocytes
20.  Cigarette smoking and airway wall thickness on CT scan in a multi-ethnic cohort: The MESA Lung Study 
Respiratory medicine  2012;106(12):1655-1664.
Background
Autopsy studies show that smoking contributes to airway wall hyperplasia and narrowing of the airway lumen. Studies of smoking and airway measures on computed tomography (CT) scan are limited to case-control studies of measures that combine airway lumen and wall thickness.
Objectives
We hypothesized that cumulative cigarette smoking would be associated with increased airway wall thickness in a large, population-based cohort.
Methods
The Multi-Ethnic Study of Atherosclerosis enrolled participants age 45-84 years from the general population. Smoking history was assessed via standardized questionnaire items; current smoking was confirmed in half the cohort with cotinine. Airway lumen and wall thickness were measured in two dimensions in posterior basal segmental bronchi on cardiac-gated CT scans. Analyses were adjusted for age, gender, genetic ancestry, education, height, weight, asthma history, particulate matter, scanner type, and scanner current.
Results
Half of the 7,898 participants had smoked and 14% were current smokers. Pack-years of smoking were associated with thicker airway walls (mean increase 0.002 mm per ten pack-years [95% CI: 0.00002, 0.004] p=0.03). Current smoking was associated with narrower airway lumens (mean decrease −0.11 mm [95% CI: −0.2, −0.02] p=0.02). There was no evidence that either association was modified by genetic ancestry, and findings persisted among participants without clinical disease.
Conclusions
Long-term cigarette smoking was associated with subclinical increases in wall thickness of sub-segmental airways whereas current smoking was associated with narrower airway lumen diameters. Smoking may contribute to airway wall thickening prior to the development of overt chronic obstructive pulmonary disease.
doi:10.1016/j.rmed.2012.08.006
PMCID: PMC3549633  PMID: 22974831
smoking; airway remodeling; Pi10; wall thickness; lumen; chronic obstructive pulmonary disease
21.  Population-Based Estimates of Transbronchial Lung Biopsy Utilization and Complications 
Respiratory medicine  2012;106(11):1559-1565.
Background
Little is known about trends in the utilization or complication rates of transbronchial lung biopsy, particularly in community hospitals.
Methods
We used the Healthcare Cost and Utilization Project Florida State Inpatient and State Ambulatory Surgical Databases to assess trends in transbronchial lung biopsy utilization in adults from 2000 to 2009. We subsequently calculated population based estimates of complications associated with transbronchial lung biopsy (iatrogenic pneumothorax and procedure-related hemorrhage) and identified characteristics associated with complications.
Results
From 2000 to 2009, the age-adjusted rate of transbronchial biopsies per 100,000 adults in Florida decreased by 25% from 74 to 55 (p<0.0001), despite stability in the overall utilization of bronchoscopy. Analysis of 82,059 procedures revealed that complications associated with transbronchial biopsy were uncommon and stable over the study period, with 0.97% (95% CI 0.94–1.01%) of procedures complicated by pneumothorax, 0.55% (95% CI 0.52–0.58%) by pneumothorax requiring chest tube placement, and 0.58% (95% CI 0.55–0.61%) by procedure-related hemorrhage. Patients with COPD (OR 1.51, 95% CI 1.31–1.75) and women (OR 1.32, 95% CI 1.15–1.52) were at increased risk for pneumothorax, while renal failure (OR 2.85, 95% CI 2.10– 3.87), cirrhosis (OR 2.31, 95% CI 1.18– 4.52), older age (OR 1.17, 95% CI 1.09–1.25) and female sex (OR 1.40, 95% CI 1.17–1.68) were associated with higher risk of procedure-related hemorrhage.
Conclusions
Utilization of transbronchial lung biopsy is decreasing relative to the overall use of bronchoscopy. Nevertheless, it remains a safe procedure with low risk of complications.
doi:10.1016/j.rmed.2012.08.008
PMCID: PMC3444528  PMID: 22938740
Bronchoscopy; transbronchial lung biopsy; health care utilization
22.  The UCSD Shortness of Breath Questionnaire has Longitudinal Construct Validity in Idiopathic Pulmonary Fibrosis 
Respiratory medicine  2012;106(10):1447-1455.
Background
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that often causes disabling dyspnea. In IPF and other lung diseases, patient-reported outcomes (PROs)—questionnaires designed to gather information from the patient's perspective—can determine whether therapies affect dyspnea or other outcomes meaningful to patients. Before a PRO can be used confidently as an outcome measure in a longitudinal trial, studies must demonstrate the PRO's ability to capture change over time in the target population. Our goal in this study was to examine whether the UCSD Shortness of Breath Questionnaire does so in patients with IPF.
Methods
We used data from the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP-IPF) to perform analyses that examined associations between UCSD scores and five external measures (anchors) at baseline and over time. Anchors included the Activity domain from St. George's Respiratory Questionnaire (SGRQ-A), the Physical Functioning domain from the SF-36 (SF36-PF), forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and distance walked during a timed walk test (6MWD). Linear regression models were used to examine relationships between UCSD scores and anchors over time.
Results
At baseline, UCSD scores were weakly correlated with percent predicted FVC (−0.21, p=0.005) and percent predicted DLCO (−0.20, p=0.008), moderately correlated with 6MWD (−0.39, p<0.0001) and strongly correlated with SGRQ-A (0.79, p<0.0001) and SF36-PF (−0.72, p<0.0001). Change over time in UCSD scores was associated with change in FVC (estimate=2.54, standard error [SE]=1.23, p=0.04), SGRQ-A (estimate=7.94, SE=1.11, p<0.0001), SF36-PF (estimate=6.00, SE=1.13, p<0.0001), and 6MWD (estimate=4.23, SE=1.18, p=0.0004) but not DLCO (estimate=0.33, SE=1.33, p=0.80).
Conclusions
These results support the validity of the UCSD to assess change in dyspnea over time in patients with IPF.
doi:10.1016/j.rmed.2012.06.018
PMCID: PMC3441137  PMID: 22801586
23.  Bronchoscopic Diagnosis of Langerhans Cell Histiocytosis and Lymphangioleiomyomatosis 
Respiratory medicine  2012;106(9):1286-1292.
Limited data are available regarding the role of bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBB) as diagnostic tools in pulmonary Langerhans’ Cell Histiocytosis (LCH) and lymphangioleiomyomatosis (LAM).
The aim of this study was to review our experience regarding the value of these two techniques in the diagnosis of these cystic lung diseases. Records of 452 patients with the presumptive diagnosis of interstitial lung disease were reviewed; 67 had a clinical-radiological diagnosis of either LCH (n=27) or LAM (n= 40). Of 16 patients with LCH who underwent BAL, four specimens (25%) contained cells which had positive immunoreactivity for CD1a. Of three patients with negative BAL fluid who had TBB, only one had a positive tissue diagnosis. Ten LCH patients were diagnosed by surgical lung biopsy of which five had negative BAL fluid. The remaining 12 patients were diagnosed by clinical and radiologic features. Standard examination of BAL fluid was of no diagnostic value in LAM. TBB was performed in seven patients and was diagnostic in six, not resulting in complications. All 13 patients who underwent surgical lung biopsies had a positive histopathologic diagnosis The remaining 21 patients were diagnosed by clinical and radiologic features. We suggest that BAL may assist in the diagnosis of LCH whereas TBB may be useful in the diagnosis of LAM, thus avoiding the need for surgical biopsy.
doi:10.1016/j.rmed.2012.06.012
PMCID: PMC3413078  PMID: 22770823
Interstitial lung diseases; fiberoptic bronchoscopy
24.  Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease 
Respiratory medicine  2012;106(7):1040-1047.
Summary
Objective
We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD).
Methods
The study sample included 74 subjects with respiratory symptoms, evaluated January 2008–January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation.
Results
The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days.
Conclusion
We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation.
doi:10.1016/j.rmed.2012.03.006
PMCID: PMC3753791  PMID: 22503074
Anti-cyclic citrullinated peptide; Rheumatoid arthritis; Interstitial lung disease; Lung diseases
25.  Obstructive sleep apnea does not promote esophageal reflux in fibrosing interstitial lung disease 
Respiratory Medicine  2012;106(7):1033-1039.
Background
In patients with fibrosing interstitial lung disease (fILD), gastroesophageal reflux (GER) is highly prevalent, perhaps because of the effects of lung fibrosis on altering intrathoracic pressure, diaphragm morphology and lower esophageal sphincter (LES) function. For unclear reasons, obstructive sleep apnea (OSA) is also highly prevalent among patients with fILD. We conducted this study to test our hypothesis that, in patients with fILD, OSA would exacerbate diaphragm/LES dysfunction and increase the propensity for—and severity of—GER.
Methods
We identified patients with fILD who underwent screening polysomnogram and pH or pH/impedence probe at our center during the same week. We examined the association between OSA and GER and used logistic regression to determine independent predictors of OSA or GER.
Results
In 54 included subjects, neither OSA (dichotomous) nor apnea hypopnea index (continuous) predicted the presence of GER. Regardless of body position (upright, recumbent), GER was no more frequent or severe among subjects with OSA vs. those without OSA. Subjects with idiopathic pulmonary fibrosis (IPF) had an odds of GER nearly seven-fold greater than subjects with other forms of fILD (odds ratio=6.84, 95% confidence interval 1.36–34.43, p=0.02). For the entire cohort and the subgroup with IPF, there was no correlation between pulmonary physiology and GER.
Conclusions
In fILD, OSA does not appear to promote GER. Research is needed to determine if compensatory mechanisms emanating from the crural diaphragm prevent GER in fILD patients with OSA and to sort out whether GER has a role in the pathogenesis of certain forms of fILD.
doi:10.1016/j.rmed.2012.03.014
PMCID: PMC3362045  PMID: 22521226

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