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1.  Large-scale international validation of the ADO index in subjects with COPD: an individual subject data analysis of 10 cohorts 
BMJ Open  2012;2(6):e002152.
Background
Little evidence on the validity of simple and widely applicable tools to predict mortality in patients with chronic obstructive pulmonary disease (COPD) exists.
Objective
To conduct a large international study to validate the ADO index that uses age, dyspnoea and FEV1 to predict 3-year mortality and to update it in order to make prediction of mortality in COPD patients as generalisable as possible.
Design
Individual subject data analysis of 10 European and American cohorts (n=13 914).
Setting
Population-based, primary, secondary and tertiary care.
Patients
COPD GOLD stages I–IV.
Measurements
We validated the original ADO index. We then obtained an updated ADO index in half of our cohorts to improve its predictive accuracy, which in turn was validated comprehensively in the remaining cohorts using discrimination, calibration and decision curve analysis and a number of sensitivity analyses.
Results
1350 (9.7%) of all subjects with COPD (60% male, mean age 61 years, mean FEV1 66% predicted) had died at 3 years. The original ADO index showed high discrimination but poor calibration (p<0.001 for difference between predicted and observed risk). The updated ADO index (scores from 0 to 14) preserved excellent discrimination (area under curve 0.81, 95% CI 0.80 to 0.82) but showed much improved calibration with predicted 3-year risks from 0.7% (95% CI 0.6% to 0.9%, score of 0) to 64.5% (61.2% to 67.7%, score of 14). The ADO index showed higher net benefit in subjects at low-to-moderate risk of 3-year mortality than FEV1 alone.
Interpretation
The updated 15-point ADO index accurately predicts 3-year mortality across the COPD severity spectrum and can be used to inform patients about their prognosis, clinical trial study design or benefit harm assessment of medical interventions.
doi:10.1136/bmjopen-2012-002152
PMCID: PMC3533065  PMID: 23242246
Pulmonary Disease, Chronic Obstructive; Mortality; Prognosis; Validation Studies
3.  Forced Expiratory Capnography and Chronic Obstructive Pulmonary Disease (COPD) 
Journal of breath research  2013;7(1):017108.
This report proposes a potentially sensitive and simple physiological method to detect early changes and to follow disease progression in obstructive pulmonary disease (COPD) based upon the usual pulmonary function test. Pulmonary function testing is a simple, although relatively insensitive, method to detect and follow COPD. As a proof-of-concept, we have examined the slope of the plateau for carbon dioxide during forced expiratory capnography in healthy (n=10) and COPD subjects (n=10). We compared the change in the rate of exhalation of carbon dioxide over time as a marker of heterogeneous ventilation of the lung. All subjects underwent pulmonary function testing, body-plethysmography, and forced exhalation capnography. The subjects with COPD also underwent high-resolution computed tomography of the chest. Regression lines were fitted to the slopes of the forced exhalation capnogram curves. There was no difference in the mean levels of exhaled carbon dioxide between the COPD and the healthy groups (p>0.48). We found a significant difference in the mean slope of the forced exhalation capnogram for the COPD subjects compared to the healthy subjects (p=0.01). Most important, for the COPD subjects, there was a significant positive correlation between the slope of the forced exhaled capnogram and a defined radiodensity measurement of the lung by high-resolution computed tomography (r2=0.49, p=0.02). The slope of the forced exhalation capnogram may be a simple way to determine physiological changes in the lungs in patients with COPD that are not obtainable with standard pulmonary function tests. Forced exhalation capnography would be of great clinical benefit if it can identify early disease changes and at-risk individuals.
doi:10.1088/1752-7155/7/1/017108
PMCID: PMC3805024  PMID: 23445906
4.  A cross-sectional study of differences in 6-min walk distance in healthy adults residing at high altitude versus sea level 
Background
We sought to determine if adult residents living at high altitude have developed sufficient adaptation to a hypoxic environment to match the functional capacity of a similar population at sea level. To test this hypothesis, we compared the 6-min walk test distance (6MWD) in 334 residents living at sea level vs. at high altitude.
Methods
We enrolled 168 healthy adults aged ≥35 years residing at sea level in Lima and 166 individuals residing at 3,825 m above sea level in Puno, Peru. Participants completed a 6-min walk test, answered a sociodemographics and clinical questionnaire, underwent spirometry, and a blood test.
Results
Average age was 54.0 vs. 53.8 years, 48% vs. 43% were male, average height was 155 vs. 158 cm, average blood oxygen saturation was 98% vs. 90%, and average resting heart rate was 67 vs. 72 beats/min in Lima vs. Puno. In multivariable regression, participants in Puno walked 47.6 m less (95% CI -81.7 to -13.6 m; p < 0.01) than those in Lima. Other variables besides age and height that were associated with 6MWD include change in heart rate (4.0 m per beats/min increase above resting heart rate; p < 0.001) and percent body fat (-1.4 m per % increase; p = 0.02).
Conclusions
The 6-min walk test predicted a lowered functional capacity among Andean high altitude vs. sea level natives at their altitude of residence, which could be explained by an incomplete adaptation or a protective mechanism favoring neuro- and cardioprotection over psychomotor activity.
doi:10.1186/2046-7648-3-3
PMCID: PMC3909455  PMID: 24484777
Six-minute walk test; High altitude adaptation; Hypoxia; Functional capacity
5.  Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD 
Human genetics  2012;132(1):79-90.
Rationale
Accelerated lung function decline is a key COPD phenotype; however its genetic control remains largely unknown.
Methods
We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European-American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry.
Measurements and Main Results
Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status.
Conclusions
We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.
doi:10.1007/s00439-012-1219-6
PMCID: PMC3536920  PMID: 22986903
COPD; lung function decline; GWAS; genome wide association; genes; polymorphisms
6.  Asthma Symptom Utility Index: Reliability, validity, responsiveness and the minimal important difference in adult asthma patients 
Background
The evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized and a minimal important difference (MID) is not established.
Objectives
We assessed the reliability, validity, and responsiveness to change of the ASUI in a population of adult asthma patients. We also sought to determine the MID for the ASUI.
Methods
Adult asthma patients (n = 1648) from two previously completed multicenter randomized trials were included. Demographic information, spirometry, ASUI scores, and other asthma questionnaire scores were obtained at baseline and during follow-up visits. Participants also kept a daily asthma diary.
Results
Internal consistency reliability of the ASUI was 0.74 (Cronbach’s alpha). Test-retest reliability was 0.76 (intra-class correlation). Construct validity was demonstrated by significant correlations between ASUI scores and Asthma Control Questionnaire (ACQ) scores (Spearman correlation r = −0.79, 95% CI [−0.85, −0.75], P<0.001) and Mini Asthma Quality of Life Questionnaire (Mini AQLQ) scores (r = 0.59, 95% CI [0.51, 0.61], P<0.001). Responsiveness to change was demonstrated, with significant differences between mean changes in ASUI score across groups of participants differing by 10% in the percent predicted FEV1 (P<0.001), and by 0.5 points in ACQ score (P < 0.001). Anchor-based methods and statistical methods support an MID for the ASUI of 0.09 points.
Conclusions
The ASUI is reliable, valid, and responsive to changes in asthma control over time. The MID of the ASUI (range of scores 0–1) is 0.09.
doi:10.1016/j.jaci.2012.07.058
PMCID: PMC3501248  PMID: 23026499
Asthma Symptom Utility Index; reliability; validity; responsiveness; minimal important difference
7.  Association of dietary soy genistein intake with lung function and asthma control: a post-hoc analysis of patients enrolled in a prospective multicentre clinical trial 
Background
Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear. Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma. A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations.
Aims
To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospective multicentre clinical trial to replicate this association.
Methods
A total of 300 study participants were included in the analysis. Dietary soy genistein intake was measured using the Block Soy Foods Screener. The level of soy genistein intake (little or no intake, moderate intake, or high intake) was compared with baseline lung function (pre-bronchodilator forced expiratory volume in 1 second (FEV1)) and asthma control (proportion of participants with an episode of poor asthma control (EPAC) and annualised rates of EPACs over a 6-month follow-up period.
Results
Participants with little or no genistein intake had a lower baseline FEV1 than those with a moderate or high intake (2.26L vs. 2.53L and 2.47L, respectively; p=0.01). EPACs were more common among those with no genistein intake than in those with a moderate or high intake (54% vs. 35% vs. 40%, respectively; p<0.001). These findings remained significant after adjustment for patient demographics and body mass index.
Conclusions
In patients with asthma, consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control.
doi:10.4104/pcrj.2012.00073
PMCID: PMC3811067  PMID: 22885561
asthma; asthma control; diet; lung function; soy genistein
8.  The Minimal Important Difference in the 6-Minute Walk Test for Patients with Pulmonary Arterial Hypertension 
Rationale: Although commonly used as the primary outcome measure of clinical trials in pulmonary arterial hypertension (PAH), the minimal important difference (MID) of the 6-minute walk test (6MWT) has not been well defined for this population of patients.
Objectives: To estimate the MID in the 6MWT in patients with PAH.
Methods: Study subjects from the clinical trial of tadalafil in PAH, a 16-week, parallel-group, randomized clinical trial of patients who were treatment naive or on background therapy with an endothelin receptor antagonist, were eligible. 6MWT was performed using a standardized protocol. Distributional and anchor-based methods were used to estimate the MID; the latter method used the Physical Component Summary Score (PCS) of the Medical Outcomes Study 36-item short form (SF-36).
Measurements and Main Results: Four hundred five subjects were analyzed. Domains of the SF-36 were weakly to modestly associated with 6MWT. Change in the PCS of the SF-36 was most strongly associated with change in 6MWT (r = 0.40, P < 0.001) and thus was selected as the anchor for subsequent anchor-based analyses. Distributional analyses yielded estimates of the MID ranging from 25.1 to 38.5 m, whereas anchor-based analyses yielded an estimate of 38.6 m.
Conclusions: Using both distributional and anchor-based methods, the estimated consensus MID in the 6MWT for PAH is approximately 33 m. These results have important implications for (1) assessing treatment responses from clinical trials and metaanalyses of specific PAH therapy, and (2) sample size calculations for future study design.
doi:10.1164/rccm.201203-0480OC
PMCID: PMC3443803  PMID: 22723290
pulmonary hypertension; outcome measures; 6-minute walk test; minimal important difference
9.  The Relation of Serum Myeloperoxidase to Disease Progression and Mortality in Patients with Chronic Obstructive Pulmonary Disease (COPD) 
PLoS ONE  2013;8(4):e61315.
Myeloperoxidase is a strong oxidant stored in primary granules of neutrophils with potent antibacterial and proatherogenic properties. Myeloperoxidase has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the relationship of myeloperoxidase to health outcomes in COPD is not well known. We measured serum myeloperoxidase levels from 4,677 subjects with mild to moderate airflow limitation in the Lung Health Study. Using a Cox proportional hazards model, we determined the relationship of serum myeloperoxidase concentration to the risk of all-cause and disease specific causes of mortality. We found that serum myeloperoxidase concentrations were significantly related to accelerated decline in forced expiratory volume in 1 second (FEV1) over 11 years of follow-up (p<0.0001), and this association persisted after adjustments for age, sex, race, baseline FEV1, and smoking status (p = 0.048). Serum myeloperoxidase concentrations were also associated with increased risk of cardiovascular mortality (p = 0.036). Individuals in the highest quintile of myeloperoxidase had a hazard ratio of cardiovascular mortality of 1.90 (95% confidence interval 1.00–3.58; p = 0.049) compared with those in the lowest quintile, which was particularly notable in patients who continued to smoke (adjusted p-value of 0.0396). However, serum myeloperoxidase concentration was not related to total mortality, respiratory mortality, or deaths from malignancies. In conclusion, increased serum myeloperoxidase levels are associated with rapid lung function decline and poor cardiovascular outcomes in COPD patients, which support the emerging role of myeloperoxidase in the pathogenesis of COPD progression and cardiovascular disease.
doi:10.1371/journal.pone.0061315
PMCID: PMC3630209  PMID: 23637811
10.  The Tiotropium Safety and Performance in Respimat® Trial (TIOSPIR®), a large scale, randomized, controlled, parallel-group trial-design and rationale 
Respiratory Research  2013;14(1):40.
Background
Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat® Soft Mist™ inhaler was at least as efficacious as tiotropium HandiHaler®, however, concerns have been raised about tiotropium’s safety when given via Respimat®.
Methods
The TIOSPIR® trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat® 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler® 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat® 5 μg once daily and Respimat® 2.5 μg once daily are non-inferior to HandiHaler® in terms of all-cause mortality, and 2). that tiotropium Respimat® 5 μg once daily is superior to HandiHaler® in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists.
Results
To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2–3 years.
Conclusion
TIOSPIR® will provide precise estimates of the relative safety and efficacy of the Respimat® and HandiHaler® formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.
doi:10.1186/1465-9921-14-40
PMCID: PMC3621103  PMID: 23547660
Tiotropium; COPD; Respimat® Soft Mist™ Inhaler; HandiHaler®
11.  Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema 
PLoS ONE  2013;8(2):e56352.
Rationale
Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema.
Methods
Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period.
Main Results
Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline.
Conclusions
MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.
doi:10.1371/journal.pone.0056352
PMCID: PMC3575373  PMID: 23441181
12.  Adherence to inhaled corticosteroids: An ancillary study of the Childhood Asthma Management Program clinical trial 
Background
Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited.
Objective
We sought to compare subjective and objective measurements of children’s adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes.
Methods
In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 μg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes.
Results
Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, −0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes.
Conclusion
Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.
doi:10.1016/j.jaci.2011.10.030
PMCID: PMC3350797  PMID: 22104610
Asthma; adherence; compliance; children; lung growth; inhaled corticosteroids; budesonide; clinical trial
13.  Asthma in the Elderly: Current Understanding and Future Research Needs 
Asthma in the elderly (AIE) is under diagnosed and under treated and there is a paucity of knowledge. The National Institute on Aging convened this workshop to identify what is known, what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of AIE. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger individuals but co-morbid illnesses and the psychosocial effects of aging may affect the diagnosis, clinical presentation and care of asthma in this population. At least two phenotypes exist among elderly asthma; those with long-standing asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiological mechanisms of AIE are likely to be different from those seen in young asthmatics and these differences may influence the clinical course and outcomes of asthma in this population.
doi:10.1016/j.jaci.2011.06.048
PMCID: PMC3164961  PMID: 21872730
Aging; airway; allergy; asthma; elderly; immune mechanisms; immunosenescence
14.  Neonatal Hyperoxia Contributes Additively to Cigarette Smoke–Induced Chronic Obstructive Pulmonary Disease Changes in Adult Mice 
The extent by which early postnatal lung injury contributes to the development of chronic obstructive pulmonary disease (COPD) in the adult is unclear. We hypothesized that exposure to hyperoxia during early postnatal life can augment lung changes caused by adult chronic cigarette smoke (CS) exposure. C57BL/6J mice (1 d old) were exposed to hyperoxia (O2) for 5 days. At 1 month of age, half of the O2–exposed mice and half of the control mice were placed in a CS chamber for 6 months. After exposure to CS, mice underwent quasi-static pressure–volume curve and mean chord length measurements; quantification of pro–Sp-c expression; and measurement of lung IL-8/ KC, CXCR2/IL8Rα, TNF-α, and IL-6 mRNA by real-time PCR. Adult mice exposed to O2+CS had significantly larger chord length measurements (P < 0.02) and lung volumes at 35 cm H2O (P < 0.05) compared with all other groups. They also had significantly less pro–Sp-c protein and surfactant protein C mRNA expression (P < 0.003). Mice exposed to O2+CS and CS-only mice had significantly higher lung resistance and longer mean time constants (P < 0.01), significantly more inflammatory cells in the bronchoalveolar lavage fluid (P < 0.03), and significantly higher levels of lung CXCR2/IL8Rα mRNA compared with mice not exposed to smoke (P < 0.02). We conclude that exposure to early postnatal hyperoxia contributed additively to CS-induced COPD changes in adult mice. These results may be relevant to a growing population of preterm children who sustained lung injury in the newborn period and may be exposed to CS in later life.
doi:10.1165/rcmb.2010-0259OC
PMCID: PMC3175575  PMID: 21239606
early postnatal hyperoxia; airspace abnormalities; chronic cigarette smoke exposure; chronic obstructive pulmonary disease
15.  Serum PARC/CCL-18 Concentrations and Health Outcomes in Chronic Obstructive Pulmonary Disease 
Rationale: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum.
Objectives: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality.
Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study.
Measurements and Main Results: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort.
Conclusions: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.
Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
doi:10.1164/rccm.201008-1220OC
PMCID: PMC3114051  PMID: 21216880
biomarker; chronic obstructive pulmonary disease; PARC/CCL-18; chemokine
16.  Effects of distance from a heavily transited avenue on asthma and atopy in a peri-urban shanty-town in Lima, Peru 
Background
Proximity to roadways increases the risk of asthma in developed countries; however, relatively little is known about this relationship in developing countries, where rapid and uncontrolled growth of cities has resulted in urban sprawl and heavy traffic volumes.
Objective
Determine the effect of distance from a heavily transited avenue on asthma symptoms and quantitative respiratory outcome measures in a peri-urban shanty town in Lima, Peru.
Methods
We enrolled 725 adolescents aged 13–15 years, administered a survey on asthma symptoms and measured spirometry, response to allergy skin testing and eNO. We calculated distances from the main avenue for all households and measured indoor PM in 100 households. We used multivariable regression to model the risk of asthma symptoms, risk of atopy, eNO and FEV1/FVC as a function of distance.
Results
Compared against 384 meters, the odds of current asthma symptoms in households living within 100 meters increased by a factor of 2 (p<0.05). The odds of atopy increased by a factor of 1.07 for every 100 meters difference in the distance from the avenue (p=0.03). We found an inverse relationship in pre-bronchodilator FEV1/FVC and distance to the avenue in females (p=0.01) but not in males. We did not find an association between eNO or household PM levels and distance.
Conclusion
Living in close proximity to a high traffic-density avenue in a peri-urban community in Peru was associated with a greater risk of asthma symptoms and atopy. Regulation of mobile source pollutants in peri-urban areas of developing countries may help reduce the burden of asthma symptoms and atopy.
doi:10.1016/j.jaci.2010.11.031
PMCID: PMC3227546  PMID: 21237505
Asthma symptoms; atopy; distance; traffic; particulate matter; spirometry
17.  The Peru Urban versus Rural Asthma (PURA) Study: methods and baseline quality control data from a cross-sectional investigation into the prevalence, severity, genetics, immunology and environmental factors affecting asthma in adolescence in Peru 
BMJ Open  2012;2(1):e000421.
Objectives
According to a large-scale international survey, Peru has one of the highest prevalences of asthma worldwide; however, data from this survey were limited to participants from urban Lima. The authors sought to characterise the epidemiology of asthma in Peru in two regions with disparate degrees of urbanisation. In this manuscript, the authors summarise the study design and implementation.
Design
A cross-sectional study.
Participants
Using census data of 13–15-year-old adolescents from two communities in Peru, the authors invited a random sample of participants in Lima (n=725) and all adolescents in Tumbes (n=716) to participate in our study.
Primary and secondary outcome measures
The authors asked participants to complete a questionnaire on asthma symptoms, environmental exposures and socio-demographics and to undergo spirometry before and after bronchodilator, skin allergy testing and exhaled nitric oxide testing. The authors obtained blood samples for haematocrit, total IgE levels, vitamin D levels and DNA in all participants and measured indoor particulate matter concentrations for 48 h in a random subset of 70–100 households at each site.
Results
Of 1851 eligible participants, 1441 (78%) were enrolled and 1159 (80% of enrolled) completed all physical tests. 1283 (89%) performed spirometry according to standard guidelines, of which 86% of prebronchodilator tests and 92% of postbronchodilator tests were acceptable and reproducible. 92% of allergy skin tests had an adequate negative control. The authors collected blood from 1146 participants (79%) and saliva samples from 148 participants (9%). Overall amounts of DNA obtained from blood or saliva were 25.8 μg, with a 260/280 ratio of 1.86.
Conclusions
This study will contribute to the characterisation of a variety of risk factors for asthma, including urbanisation, total IgE levels, vitamin D levels and candidate genes, in a resource-poor setting. The authors present data to support high quality of survey, allergic, spirometric and genetic data collected in our study.
Article summary
Article focus
We sought to characterise the epidemiology of asthma in Peru by studying two regions with disparate degrees of urbanisation.
We summarise the study design, implementation and standard operating procedures and provide quality control data for important outcome and exposure variables.
Key messages
We present data to support high quality of survey, allergic, spirometric and genetic data collected in our study.
Strengths and limitations of this study
This study will contribute to the characterisation of a variety of risk factors for asthma, including urbanisation, total IgE levels, vitamin D levels and candidate genes, in a resource-poor setting.
This study is cross-sectional and therefore does not track symptoms over time to directly determine causality. In addition, we did not collect stool samples to assess parasitic infections nor do we have information on respiratory infections in early childhood.
doi:10.1136/bmjopen-2011-000421
PMCID: PMC3289983  PMID: 22357570
18.  The Madison Avenue Effect: How drug presentation style influences adherence and outcome in patients with asthma 
Background
Little is known about how drug presentation influences medication adherence.
Objective
Examine the effect of an educational program aimed at increasing expectations of treatment benefit on medication adherence.
Methods
Data are analyzed from 99 participants who underwent electronic drug monitoring during TAPE (Trial of Asthma Patient Education), a randomized placebo-controlled multi-center trial. Participants with suboptimally-controlled asthma were randomized to placebo or montelukast in conjunction with a presentation mode that was either neutral or designed to increase outcome expectancy. Adherence was monitored electronically over 4 weeks, and was defined as ≥ 80% use of prescribed doses. Outcome expectancy, peak expiratory flow, pre-bronchodilator forced expiratory volume, asthma control (ACQ), and asthma-related quality of life were assessed at baseline and at the 4-week follow-up.
Results
Average electronic medication adherence was 69.9%. There was a significant interaction between presentation mode and drug assignment, with participants in the enhanced/montelukast group having a higher change in outcome expectancy (Δ 2.1 points, p < 0.001) and better medication adherence (odds ratio 4.0, CI 1.1, 14.3) compared to those in the neutral/placebo group. There was no difference in asthma symptoms, quality of life, or clinical outcomes based on presentation mode. Rather, increased outcome expectancy was associated with modest improvements in asthma symptoms after adjusting for presentation mode, drug assignment, and medication adherence.
Conclusion
The use of an enhanced presentation aimed at increasing outcome expectancy may lead to improved medication adherence.
doi:10.1016/j.jaci.2010.11.038
PMCID: PMC3050545  PMID: 21281871
Asthma; medication adherence; electronic monitoring; outcome expectancy; behavioral intervention
19.  Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases 
Molecular Medicine  2012;18(1):445-454.
α-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke–induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL–deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation.
doi:10.2119/molmed.2011.00207
PMCID: PMC3356416  PMID: 22245800
20.  The Relationship of Asthma-Specific Quality of Life During Pregnancy to Subsequent Asthma and Perinatal Morbidity 
Objective
To determine whether asthma-specific quality of life during pregnancy is related to asthma exacerbations and to perinatal outcomes.
Methods
This was a secondary analysis of data from a randomized controlled trial of inhaled beclomethasone versus theophylline in the treatment of moderate asthma during pregnancy. The Juniper Asthma Quality of Life Questionnaire (AQLQ) was administered to patients at enrollment. Exacerbations were defined as asthma symptoms requiring a hospitalization, unscheduled medical visit, or oral corticosteroid course.
Results
Quality of life assessments were provided by 310 of the 385 participants who completed the study. There was more than a 25% decrease in the odds of a subsequent asthma exacerbation for every 1-point increase in AQLQ score for the overall score (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.55–0.96), emotion domain (OR 0.72, 95% CI 0.59–0.88), and symptoms domain (OR 0.73, 95% CI 0.57–0.94). These relationships were not significantly influenced by initial symptom frequency or forced expiratory volume in 1 s (FEV1). No significant relationships were demonstrated between enrollment AQLQ scores and preeclampsia, preterm birth, low birth weight, or small for gestational age.
Conclusion
Asthma-specific quality of life in early pregnancy is related to subsequent asthma morbidity during pregnancy but not to perinatal outcomes.
doi:10.3109/02770900903483758
PMCID: PMC3249656  PMID: 20100020
asthma; exacerbations; perinatal outcomes; pulmonary function; quality of life
21.  Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice 
Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β–specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β–targeted therapies for patients with COPD.
doi:10.1172/JCI46215
PMCID: PMC3248282  PMID: 22182843
22.  Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients 
The Journal of Clinical Investigation  2011;121(11):4289-4302.
Chronic obstructive pulmonary disease (COPD), which is caused primarily by cigarette smoking, is a major health problem worldwide. The progressive decline in lung function that occurs in COPD is a result of persistent inflammation of the airways and destruction of the lung parenchyma. Despite the key role of inflammation in the pathogenesis of COPD, treatment with corticosteroids — normally highly effective antiinflammatory drugs — has little therapeutic benefit. This corticosteroid resistance is largely caused by inactivation of histone deacetylase 2 (HDAC2), which is critical for the transrepressive activity of the glucocorticoid receptor (GR) that mediates the antiinflammatory effect of corticosteroids. Here, we show that in alveolar macrophages from patients with COPD, S-nitrosylation of HDAC2 is increased and that this abolishes its GR-transrepression activity and promotes corticosteroid insensitivity. Cys-262 and Cys-274 of HDAC2 were found to be the targets of S-nitrosylation, and exogenous glutathione treatment of macrophages from individuals with COPD restored HDAC2 activity. Treatment with sulforaphane, a small-molecule activator of the transcription factor nuclear factor erythroid 2–related factor 2 (NRF2), was also able to denitrosylate HDAC2, restoring dexamethasone sensitivity in alveolar macrophages from patients with COPD. These effects of sulforaphane were glutathione dependent. We conclude that NRF2 is a novel drug target for reversing corticosteroid resistance in COPD and other corticosteroid-resistant inflammatory diseases.
doi:10.1172/JCI45144
PMCID: PMC3204828  PMID: 22005302
23.  Physical Activity, Health Status and Risk of Hospitalization in Patients with Severe Chronic Obstructive Pulmonary Disease 
Respiration  2010;80(1):10-18.
Background
Chronic obstructive pulmonary disease (COPD) is a leading cause of death and 70% of the cost of COPD is due to hospitalizations. Self-reported daily physical activity and health status have been reported as predictors of a hospitalization in COPD but are not routinely assessed.
Objectives
We tested the hypothesis that self-reported daily physical activity and health status assessed by a simple question were predictors of a hospitalization in a well-characterized cohort of patients with severe emphysema.
Methods
Investigators gathered daily physical activity and health status data assessed by a simple question in 597 patients with severe emphysema and tested the association of those patient-reported outcomes to the occurrence of a hospitalization in the following year. Multiple logistic regression analyses were used to determine predictors of hospitalization during the first 12 months after randomization.
Results
The two variables tested in the hypothesis were significant predictors of a hospitalization after adjusting for all univariable significant predictors: >2 h of physical activity per week had a protective effect [odds ratio (OR) 0.60; 95% confidence interval (95% CI) 0.41–0.88] and self-reported health status as fair or poor had a deleterious effect (OR 1.57; 95% CI 1.10–2.23). In addition, two other variables became significant in the multivariate model: total lung capacity (every 10% increase) had a protective effect (OR 0.88; 95% CI 0.78–0.99) and self-reported anxiety had a deleterious effect (OR 1.75; 95% CI 1.13–2.70).
Conclusion
Self-reported daily physical activity and health status are independently associated with COPD hospitalizations. Our findings, assessed by simple questions, suggest the value of patient-reported outcomes in developing risk assessment tools that are easy to use.
doi:10.1159/000296504
PMCID: PMC2889264  PMID: 20234126
Activity of daily living; Chronic obstructive pulmonary disease; Emphysema; Outcomes; Quality of life; Health status; Exercise
24.  Prevalence and risk factors for unrecognized obstructive lung disease among urban drug users 
Background
Obstructive lung disease (OLD) is frequently unrecognized and undertreated. Urban drug users are at higher risk for OLD due to race, behavioral, and socioeconomic characteristics, yet little data exist on prevalence and risk factors associated with unrecognized OLD in this population.
Objective
The objective of this study is to determine the prevalence of unrecognized OLD in an urban population and identify the characteristics associated with lack of physician-diagnosed OLD.
Design
Cross-sectional analysis from the Acquired Immunodeficiency Syndrome Linked to the Intravenous Experience (ALIVE) study, an observational study of current and former injection drug users in Baltimore, Maryland, USA.
Participants
All participants with spirometry-defined airflow obstruction were stratified by the presence or absence of physician diagnosis of OLD.
Main measures
Using cross-sectional demographic, clinical, and spirometric measurements, multivariable regression models were generated to identify factors independently associated with unrecognized OLD.
Key results
Of the 1083 participants evaluated in the ALIVE lung substudy, 176 (16.3%) met spirometric criteria for OLD. Of those, only 88 (50%) had a physician diagnosis of OLD. The prevalence of unrecognized OLD decreased as severity of airflow obstruction increased. Factors independently associated with unrecognized OLD were absence of respiratory symptoms (prevalence ratio [PR], 1.70; 95% confidence interval [CI]: 1.29–2.23; P < 0.01) and less severe dyspnea (PR, 0.83; 95% CI: 0.72–0.96, per point increase in dyspnea scale; P = 0.01). In the subset of human immunodeficiency virus (HIV)–infected participants, the use of antiretroviral therapy (ART) was independently associated with an increased prevalence of unrecognized OLD (PR, 1.93; 95% CI: 1.05–3.56; P = 0.03).
Conclusions
In a cohort of current and former urban drug users, OLD is substantially underrecognized and associated with lack of respiratory symptoms. Relying on the presence of respiratory symptoms as a trigger to perform spirometry may result in a substantial underdiagnosis of OLD in this population. HIV-infected individuals receiving ART are a population particularly vulnerable to unrecognized OLD.
doi:10.2147/COPD.S15968
PMCID: PMC3048084  PMID: 21407821
obstructive lung disease; human immunodeficiency virus infection; COPD; asthma; spirometry
25.  Long Term Effects of Cyclophosphamide Treatment on Lung Function and Survival in Scleroderma Patients with Interstitial Lung Disease 
Background:
Scleroderma (SSc) patients with active interstitial lung disease (ILD) experience a decline in lung function and increased mortality; cyclophosphamide (CYC) therapy may stabilize lung function at one and two years follow-up. Long-term lung function and survival outcomes of SSc patients with ILD following CYC treatment remain largely unknown.
Methodology:
We reviewed records of SSc patients with active ILD who had received at least six months of CYC treatment and had pulmonary function tests (PFTs) performed at least two years from the onset of treatment.
Principal Findings:
Thirty eight patients meeting eligibility criteria had a mean follow-up period from start of CYC to the last follow-up PFT of 5.1 years (range 2.3 -10.8 years). At a median of 4.1 years (range 9 months - 8.4 years), 12/38 (32%) patients had a significant decline in % predicted Forced Vital Capacity from their baseline PFT. At a median of 3.9 years (range 7 months - 8.4 years); 12/36 (33%) patients experienced a significant decline in their % predicted carbon monoxide diffusing capacity. Three patients died at a follow-up between 4.5-6 years and two received bilateral lung transplants because of severe restrictive lung disease.
Conclusions:
While the majority of SSc patients treated with CYC for active ILD experience long-term lung function stability and survive, greater than 1/3 of patients will experience either lung function decline, death, or require a lung transplant. This suggests that despite aggressive immune suppressing therapy, a subset of patients will have continued lung function decline, highlighting the need for ongoing monitoring and better therapeutic options.
doi:10.2174/1874312901105010001
PMCID: PMC3087310  PMID: 21552414
Scleroderma; pulmonary fibrosis; cyclophosphamide.

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