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1.  Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans 
Background
COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD.
Methods
We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene® cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW).
Results
Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack-years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms).
Conclusions
Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non-Hispanic Whites.
doi:10.15326/jcopdf.1.1.2014.0112
PMCID: PMC4329763
COPD; Comorbidities; Race
2.  Racial Differences in CT Phenotypes in COPD 
COPD  2013;10(1):20-27.
Background
Whether African Americans (AA) are more susceptible to COPD than non-Hispanic Whites (NHW) and whether racial differences in disease phenotype exist is controversial. The objective is to determine racial differences in the extent of emphysema and airway remodeling in COPD.
Methods
First, 2,500 subjects enrolled in the COPDGene study were used to evaluate racial differences in quantitative CT (QCT) parameters of % emphysema, air trapping and airway wall thickness. Independent variables studied included race, age, gender, education, BMI, pack-years, smoking status, age at smoking initiation, asthma, previous work in dusty job, CT scanner and center of recruitment.
Results
Of the 1,063 subjects with GOLD Stage II-IV COPD, 200 self-reported as AA. AAs had a lower mean % emphysema (13.1 % vs. 16.1%, p = 0.005) than NHW and proportionately less emphysema in the lower lung zones. After adjustment for covariates, there was no statistical difference by race in air trapping or airway wall thickness. Measured QCT parameters were more predictive of poor functional status in NHWs compared to AAs.
Conclusions
AAs have less emphysema than NHWs but the same degree of airway disease. Additional factors not easily assessed by current QCT techniques may account for the poor functional status in AAs.
doi:10.3109/15412555.2012.727921
PMCID: PMC4321889  PMID: 23413893
Airway wall thickness; Air trapping; Chronic obstructive pulmonary disease; Emphysema; Quantitative CT; Race
3.  Hepatitis C Virus Infection Is Not An Independent Risk Factor For Obstructive Lung Disease 
COPD  2013;11(1):10-16.
Several epidemiological studies have suggested that hepatitis C virus (HCV) infection is associated with the presence of obstructive lung disease (OLD). However, there is a strong link between HCV infection and tobacco abuse, a major risk factor for the development of OLD. In this study we analyzed clinical, laboratory and spirometric data from 1068 study participants to assess whether HCV infection, viremia, or HCV-associated end organ damage were associated with OLD. Demographics, risk behavior, serologic status for HCV and HIV, and spirometric measurements were collected from a cross-sectional analysis of the Acquired Immunodeficiency Syndrome (AIDS) Linked to the IntraVenous Experience (ALIVE) study, an observational cohort of IDUs followed in Baltimore, MD since 1988. Of 1,068 participants, 890 (83%) were HCV positive and 174 (16%) met spirometric criteria for OLD. Factors independently associated with OLD were age and BMI. HCV infection, viral load and HCV-associated end organ damage were similar in participants with and without OLD. In summary, there was no independent association between markers of HCV exposure, chronicity, viremia, or HCV-associated end-organ damage with OLD. Our findings support the strong correlation between HCV status, injection drug use, and smoking. These data suggest that HCV may not be a sole contributor to the increased prevalence of OLD described in previous studies of HCV-infected individuals.
doi:10.3109/15412555.2013.800854
PMCID: PMC4302731  PMID: 23862666
chronic viral infections; injection drug users; HIV; Obstructive Lung Disease
4.  FValidation and Psychometric Properties of the Asthma Control Questionnaire among Children 
The Journal of allergy and clinical immunology  2013;133(1):10.1016/j.jaci.2013.06.029.
Background
The Asthma Control Questionnaire (ACQ) is a patient-centered tool for evaluating asthma control. It has been validated in adults but not well-validated among children.
Objective
We evaluated the reliability, validity, and responsiveness to change of the ACQ for assessing asthma control in children ages 6 to 17. A threshold value for poor disease control and a minimally important difference (MID) were also determined.
Methods
Data from 305 asthmatic children enrolled in a clinical trial were examined. The ACQ was administered at 8 visits. We analyzed results for the combined age group and for age groups 6 to 11 and 12 to 17 separately.
Results
Overall, the Cronbach’s alpha (internal consistency) for the ACQ was 0.74 at baseline, and the intraclass correlation coefficient (test-retest reliability) for repeated questionnaires among stable patients was 0.53. The Pearson correlations between the ACQ and other asthma questionnaires were moderate to strong (−0.64 to −0.73). Mean ACQ scores were higher (worse) in patients whose peak flow decreased, who used more rescue medications, or who sought medical care for asthma than in patients who were stable (P<0.0001 for all measures). Change in ACQ scores were significantly different among patients with deteriorating, improving, or stable asthma symptoms (P ≤0.01). The optimal threshold indicating poor asthma control was ≥1.25. The MID was established to be 0.40. Results for the separate age groups were similar.
Conclusion
The ACQ is a moderately reliable, valid, and responsive tool with adequate psychometric properties for assessing recent asthma control among children.
doi:10.1016/j.jaci.2013.06.029
PMCID: PMC3874246  PMID: 23932458
asthma; asthma control; Asthma Control Questionnaire; validity; minimally important difference
5.  Transcriptional responses of neonatal mouse lung to hyperoxia by Nrf2 status 
Cytokine  2013;65(1):10.1016/j.cyto.2013.09.021.
Hyperoxia exposure can inhibit alveolar growth in the neonatal lung through induction of p21/ p53 pathways and is a risk factor for the development of bronchopulmonary dysplasia (BPD) in preterm infants. We previously found that activation of nuclear factor erythroid 2 p45-related factor (Nrf2) improved survival in neonatal mice exposed to hyperoxia likely due to increased expression of anti-oxidant response genes. It is not known however, whether hyperoxic induced Nrf2 activation attenuates the growth impairment caused by hyperoxia in neonatal lung. To determine if Nrf2 activation modulates cell cycle regulatory pathway genes associated with growth arrest we examined the gene expression in the lungs of Nrf2−/− and Nrf2+/+ neonatal mice at one and three days of hyperoxia exposure.
Methods
Microarray analysis was performed in neonatal Nrf2+/+ and Nrf2−/− lungs exposed to one and three days of hyperoxia. Sulforaphane, an inducer of Nrf2 was given to timed pregnant mice to determine if in utero exposure attenuated p21 and IL-6 gene expression in wildtype neonatal mice exposed to hyperoxia.
Results
Cell cycle regulatory genes were induced in Nrf2−/− lung at one day of hyperoxia. At 3 days of hyperoxia, induction of cell cycle regulatory genes was similar in Nrf2+/+ and Nrf2−/− lungs, despite higher inflammatory gene expression in Nrf2−/− lung.
Conclusion
p21/ p53 pathways gene expression was not attenuated by Nrf2 activation in neonatal lung. In utero SUL did not attenuate p21 expression in wildtype neonatal lung exposed to hyperoxia. These findings suggest that although Nrf2 activation induces expression of antioxidant genes, it does not attenuate alveolar growth arrest caused by exposure to hyperoxia.
doi:10.1016/j.cyto.2013.09.021
PMCID: PMC3875154  PMID: 24139870
Alveolar growth inhibition; cell cycle regulatory genes; inflammation; hyperoxia; chronic lung disease of prematurity; bronchopulmonary dysplasia neonatal lung; nuclear factor erythroid 2 p45-related factor
6.  Risk Factors for Montelukast Treatment Failure in Step-Down Therapy for Controlled Asthma 
Background
Leukotriene receptor antagonists including montelukast are an option for step-down therapy for mild asthmatics controlled on low-dose inhaled corticosteroids (ICS). Because some patients fail montelukast step-down therapy, it would be helpful for clinicians to be able to predict the risk of treatment failure.
Objectives
To determine patient characteristics associated with montelukast treatment failure and develop a clinical index to predict the risk of montelukast treatment failure.
Methods
Using the 165 participants in the Leukotriene or Corticosteroid or Corticosteroid-Salmeterol Study (LOCCS) trial who were stepped down from low-dose ICS to montelukast, we determined associations between enrollment variables and treatment failure. We constructed a montelukast failure index to predict the risk of montelukast treatment failure during step-down. To assess its specificity for montelukast, index performance was evaluated in the other LOCCS treatment groups.
Results
Characteristics independently associated with montelukast treatment failure included age of asthma onset <10 years old (OR = 2.39; 95% CI = 1.17–5.02; p = .018), need for steroid burst in the last year (OR = 2.39; 95% CI = 1.13–5.09; p = .022), and pre-bronchodilator forced expiratory volume in 1 s (FEV1) (OR = 1.44 per 10% lower % predicted; 95% CI = 1.07–1.97; p = .016). A montelukast failure index was generated from these three variables (range: −5 to 7 points). Scores <0 predicted low risk (<0.20) of treatment failure, whereas scores >5 predicted high risk (>0.60) of treatment failure.
Conclusion
Early asthma onset, worse asthma control in the last year, and lower pre-bronchodilator FEV1 are associated with montelukast treatment failure. A montelukast failure index is proposed to quantify the risk of failure prior to treatment initiation.
doi:10.3109/02770903.2011.627488
PMCID: PMC4277696  PMID: 22029858
asthma; leukotrienes; therapy
7.  A Simplified Score to Quantify Comorbidity in COPD 
PLoS ONE  2014;9(12):e114438.
Importance
Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes.
Materials and Methods
Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS.
Results
Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341).
Conclusions
Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD.
doi:10.1371/journal.pone.0114438
PMCID: PMC4267736  PMID: 25514500
8.  Club Cell Protein 16 and Disease Progression in Chronic Obstructive Pulmonary Disease 
Rationale: Club (Clara) cell protein 16 (CC-16) is a protein that is synthesized predominantly in the lungs and is detectable in serum. Its expression decreases with lung injury and smoking, and is thus a marker of bronchial cell dysfunction.
Objectives: To evaluate the possibility of using serum CC-16 as a biomarker for disease progression in chronic obstructive pulmonary disease (COPD).
Methods: We measured serum CC-16 levels from 4,724 subjects with mild-to-moderate airflow limitation in the Lung Health Study. Using a linear regression model, we determined the relationship of serum CC-16 concentrations to decline in lung function over 9 years. In addition, to determine whether CC-16 plays a major role in the pathogenesis of mild COPD, we exposed CC-16–deficient (−/−) mice to 6 months of cigarette smoke.
Measurements and Main Results: Reduced serum concentrations of CC-16 were associated with accelerated decline in FEV1 over 9 years (P < 0.0001), and this association persisted after adjustments for age, sex, race, smoking status, airway reactivity, body mass index, and baseline FEV1 (P = 0.0002). However, CC-16−/− mice did not demonstrate an enhanced risk of emphysema or small airway remodeling in response to cigarette smoke.
Conclusions: Serum CC-16 is associated with disease progression, and may assist in the identification of “rapid progressors.” However, the absence of CC-16 does not appear to modify the risk of cigarette-related COPD in mice.
doi:10.1164/rccm.201305-0892OC
PMCID: PMC3917377  PMID: 24245748
biomarker; chronic obstructive pulmonary disease; disease progression; smoking
9.  Asthma Outcomes: Pulmonary Physiology 
Background
Outcomes of pulmonary physiology have a central place in asthma clinical research.
Objective
At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons.
Methods
Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.
Results
A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and pre- and post-bronchodilator FEV1 also are core outcomes for study population characterization and observational studies.
Conclusions
The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research.
doi:10.1016/j.jaci.2011.12.986
PMCID: PMC4263032  PMID: 22386510
Spirometry; airway responsiveness; peak expiratory flow monitoring; lung volumes; gas exchange
11.  Factors to Inform Clinicians About the End of Life in Severe Chronic Obstructive Pulmonary Disease 
Journal of pain and symptom management  2013;46(4):491-499.e4.
Context
Palliative services have historically been offered to terminal cancer patients, but much less so in other chronic illnesses like chronic obstructive pulmonary disease (COPD) because of difficulties in predicting the trajectory to death.
Objectives
The goal of this study was to determine if the change over time of key parameters (trajectory) in severe COPD patients can independently predict short-term mortality.
Methods
We analyzed data from 1218 patients with severe COPD. Multivariate models for trajectory change were used to forecast mortality at 12 months.
Results
Changes in several variables by defined cutpoints increase significantly and independently the odds of dying in 12 months. The earliest and strongest predictors were the decrease in gait speed by 0.14 m/sec or six-minute walk by 50m (OR 4.40, P<0.0001). Alternatively, if six-minute walk or gait speed were not used, change toward perceiving a very sedentary -state using single question- (OR 3.56, p=0.0007)and decrease in maximal inspiratory pressure >11 cm H2O (OR 2.19, p=0.0217). Then, and change toward feeling upset or downhearted (OR 2.44, p=0.0250), decrease in room air resting PaO2 >5 mmHg (OR 2.46, p=0.0156), increase in room air resting PaCO2 >3 mmHg (OR 2.8, p=0.0039). Change over time models were more discriminative (lower c-statistics) than change form baseline models.
Conclusion
The changes in defined variables and patient-reported outcomes by defined cutpoints were independently associated with increased 12-month mortality in patients with severe COPD. These results may inform clinicians when to initiate end-of-life communications and palliative care.
doi:10.1016/j.jpainsymman.2012.10.283
PMCID: PMC3728164  PMID: 23522520
Chronic obstructive pulmonary disease; severe COPD; end-stage COPD; palliative care; end-of-life care; gait speed; mortality; prediction tools
12.  Randomized Clinical Trial of Lansoprazole for Poorly Controlled Asthma in Children 
Context
Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. It is not known whether treatment of GER with a proton-pump inhibitor (PPI) improves asthma control.
Objective
To determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.
Design, Setting, and Patients
A multicenter, randomized, masked, placebo controlled, parallel clinical trial comparing lansoprazole to placebo in children with poor asthma control on inhaled corticosteroid treatment conducted at 18 academic clinical centers. Participants were followed for 24 weeks. A subgroup had an esophageal pH study before randomization.
Intervention
Children received either lansoprazole (15 mg daily < 30 kg; 30 mg ≥ 30 kg) or placebo, 1:1 allocation ratio.
Main outcome
The primary outcome was the change in Asthma Control score (ACQ, range from 0 to 6). Secondary outcomes included lung function measures, asthma-related quality of life and acute episodes of poor asthma control.
Results
306 children were enrolled from April 2011 to August 2010, the median age was 11. The mean change (95% confidence interval (CI)) in the ACQ score was −0.1 (−0.2, 0.1) and −0.2 (−0.4, −0.1) units for the lansoprazole and placebo groups, respectively (P=0.12). There were no detectable treatment differences in secondary outcomes (mean (95% CI) for FEV1(0.00 (−0.08, 0.08)), asthma quality of life (−0.1 (−0.4, 0.1) or episodes of poor asthma control, hazard ratio of 1.18 (95% CI 0.91, 1.53). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole versus placebo was observed for any asthma outcome. Children treated with lansoprazole reported more upper respiratory infections (63% vs 49%, P=0.02), sore throats (52% vs 39%, P=0.02), and bronchitis (7% vs 2%, P=0.05).
Conclusion
Among children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, as compared to placebo, did not improve symptoms nor lung function but was associated with increased adverse events.
doi:10.1001/jama.2011.2035
PMCID: PMC4153372  PMID: 22274684
13.  Obesity in Children with Poorly-Controlled Asthma: Sex Differences 
Pediatric pulmonology  2012;48(9):847-856.
Background
Obesity increases asthma risk, and may alter asthma severity. In adults, sex appears to modify the effect of obesity on asthma. Among children, the effect of sex on the relationship between obesity and asthma severity remains less clear, particularly when considering race.
Objective
To determine how obesity affects disease characteristics in a diverse cohort of children with poorly controlled asthma, and if obesity effects are altered by sex.
Design
We analyzed 306 children between 6–17 years of age with poorly controlled asthma enrolled in a 6-month trial assessing lansoprazole for asthma control. In this secondary analysis, we determined associations between obesity and symptom severity, spirometry, exacerbation risk, airway biomarkers, bronchial reactivity and airflow perception. We used both a multivariate linear regression and longitudinal mixed-effect model to determine if obesity interacted with sex to affect asthma severity.
Results
Regardless of sex, BMI>95th percentile did not affect asthma control, exacerbation risk or airway biomarkers. Sex changed the effect of obesity on lung function (sex*obesity FEV1%, interaction p-value <.01, sex*obesity FEV1/FVC, interaction p-value=.03). Obese males had significantly worse airflow obstruction compared to non-obese males, while in females there was no obesity effect on airflow obstruction. In females, obesity was associated with significantly greater FEV1 and FVC, and a trend toward reduced airway reactivity.
Conclusions
Obesity did not affect asthma control, airway markers or disease stability; however obesity did affect lung function in a sex-dependent manner. In males, obesity associated with reduced FEV1/FVC, and in females, obesity associated with substantially improved lung function.
doi:10.1002/ppul.22707
PMCID: PMC3578966  PMID: 23143849
Asthma; Obesity; Children; Sex; Body Mass Index; Spirometry
14.  Association between obstructive lung disease and markers of HIV infection in a high-risk cohort 
Thorax  2011;67(4):309-314.
Background
Evidence suggests an association between HIV infection and the presence of obstructive lung disease (OLD). However, the associations between specific markers of HIV infection and OLD remain unclear. A study was undertaken to determine the independent associations of HIV infection, CD4 cell count and plasma HIV viral load with the presence of OLD in an urban cohort.
Methods
Clinical, laboratory and spirometric data from the AIDS Linked to the Intravenous Experience (ALIVE) study, an observational study of current and former injection drug users in Baltimore, Maryland, were analysed. Multivariable logistic regression models were generated to identify HIV infection indices independently associated with OLD.
Results
Of 1077 participants (mean±SD age 48±8 years), 89% were African-American, 65% were men and 86% were current smokers. A total of 303 (28%) were HIV infected and 176 (16%) had spirometry-defined OLD. Higher viral load was independently associated with OLD. HIV-infected individuals with viral load >200 000 copies/ml had a 3.4-fold increase in the odds of OLD compared with HIV-negative participants (95% CI 1.24 to 9.39; p=0.02). The association between higher HIV viral load and OLD persisted after accounting for antiretroviral therapy use (OR 4.06, 95% CI 1.41 to 11.7; p=0.01). No association was observed between HIV serostatus or CD4 cell count and the presence of OLD.
Conclusion
In a cohort at risk for OLD and HIV infection, high viral load but not CD4 cell count was associated with an increased prevalence of spirometry-defined OLD. These findings suggest that higher viral load may contribute mechanistically to the increased risk of OLD in patients with HIV infection.
doi:10.1136/thoraxjnl-2011-200702
PMCID: PMC4135473  PMID: 22090038
15.  The chloroplast. Basics and applications 
Annals of Botany  2013;112(3):vii.
doi:10.1093/aob/mct115
PMCID: PMC3718209
16.  A randomized study of contingency management and spirometric lung age for motivating smoking cessation among injection drug users 
BMC Public Health  2014;14(1):761.
Background
Even after quitting illicit drugs, tobacco abuse remains a major cause of morbidity and mortality in former injection drug users. An important unmet need in this population is to have effective interventions that can be used in the context of community based care. Contingency management, where a patient receives a monetary incentive for healthy behavior choices, and incorporation of individual counseling regarding spirometric “lung age” (the age of an average healthy individual with similar spirometry) have been shown to improve cessation rates in some populations. The efficacy of these interventions on improving smoking cessation rates has not been studied among current and former injection drug users.
Methods
In a randomized, factorial design study, we recruited 100 active smokers from an ongoing cohort study of current and former injection drug users to assess the impact of contingency management and spirometric lung age on smoking cessation. The primary outcome was 6-month biologically-confirmed smoking cessation comparing contingency management, spirometric lung age or both to usual care. Secondary outcomes included differences in self-reported and biologically-confirmed cessation at interim visits, number of visits attended and quit attempts, smoking rates at interim visits, and changes in Fagerstrom score and self-efficacy.
Results
Six-month biologically-confirmed smoking cessations rates were 4% usual care, 0% lung age, 14% contingency management and 0% for combined lung age and contingency management (p = 0.13). There were no differences in secondary endpoints comparing the four interventions or when pooling the lung age groups. Comparing contingency management to non-contingency management, 6-month cessation rates were not different (7% vs. 2%; p = 0.36), but total number of visits with exhaled carbon monoxide-confirmed abstinence were higher for contingency management than non-contingency management participants (0.38 vs. 0.06; p = 0.03), and more contingency management participants showed reduction in their Fagerstrom score from baseline to follow-up (39% vs. 18%; p = 0.03).
Conclusions
While lung age appeared ineffective, contingency management was associated with more short-term abstinence and lowered nicotine addiction. Contingency management may be a useful tool in development of effective tobacco cessation strategies among current and former injection drug users.
Trial registration
Clinicaltrials.gov NCT01334736 (April 12, 2011).
doi:10.1186/1471-2458-14-761
PMCID: PMC4132916  PMID: 25074396
Contingency management; Spirometry; Lung age; Smoking cessation
17.  HIV and COPD: impact of risk behaviors and diseases on quality of life 
Purpose
Smoking worsens quality of life among HIV-infected individuals, but it remains unclear if this association is related simply to smoking or to chronic obstructive pulmonary disease (COPD), the end-organ disease caused by smoking.
Methods
Using cross-sectional data from the AIDS Linked to the Intravenous Experience study, we determined the independent effects of smoking, HIV and COPD assessed using the Medical Outcome Studies-HIV questionnaire.
Results
Of 973 participants, 287 (29.5%) were HIV infected and 151 (15.5%) had spirometry-defined obstruction. Eight hundred and thirty-four (85.7%) were current smokers with 23.3 mean pack-years history. HIV infection was independently associated with reduced physical and mental health. COPD was associated with a trend toward worse physical health (−1.48 units; 95%CI −3.33 to 0.38; p = 0.12) and was independently associated with worse mental health (−2.43 units; 95%CI −4.22 to −0.64; p < 0.01). After accounting for COPD and other covariates, smoking was not associated with changes in physical or mental health.
Conclusions
The presence of COPD, rather than smoking, is associated with worse quality of life independent of HIV infection. Diagnosis and management of COPD in former or current smokers with or at risk for HIV may further improve quality of life.
doi:10.1007/s11136-010-9701-x
PMCID: PMC4097077  PMID: 20617387
Quality of life; Chronic obstructive pulmonary disease; Human immunodeficiency virus; Injection drug use; Smoking; Tobacco use
18.  Changes in Estimated Right Ventricular Systolic Pressure Predict Mortality and Pulmonary Hypertension in a Cohort of Scleroderma Patients 
Annals of the rheumatic diseases  2012;72(7):10.1136/annrheumdis-2012-201861.
Objectives
Annual echocardiography screening is widely used in scleroderma, but the utility of longitudinal assessment is unknown. Accordingly, we evaluated whether change in right ventricular systolic pressure (RVSP) was a risk factor for mortality and development of pulmonary arterial hypertension (PAH) in a cohort of scleroderma patients.
Methods
The study population consisted of scleroderma patients who had at least 3 echocardiograms and pulmonary function tests (PFTs) over ≥1 year as part of routine care. The annual rate of change in RVSP was determined for each subject. Cox proportional hazards regression was performed to assess the association between PAH and mortality, and change in RVSP/year, adjusted for relevant covariates.
Results
613 scleroderma patients with 3244 echocardiograms were studied. The adjusted relative hazards of PAH and mortality were 1.08 (95% CI 1.05,1.11) and 1.12 (95% CI 1.08,1.15) per 1mmHg increase in RVSP/year, respectively. Compared to patients with a stable RVSP, the relative hazards for development of PAH was 1.90 (95% CI 0.91,3.96), 5.09 (95% CI 2.53,10.26) and 6.15 (95% CI 3.58,10.56) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+mmHg/year. Compared to the same reference group, the relative hazards for death was 0.92 (95% CI 0.48,1.73), 2.16 (95% CI 1.16,4.01), and 5.05 (95% CI 3.47,7.34) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99, and 3+mmHg/year.
Conclusions
In a population of scleroderma patients, the rate of increase in RVSP is a risk factor for mortality and PAH even after adjustment for clinical characteristics and longitudinal PFT data.
doi:10.1136/annrheumdis-2012-201861
PMCID: PMC3839570  PMID: 22887850
Systemic Sclerosis; Pulmonary Hypertension; Echocardiography
19.  ALOX5 Polymorphism Associates with Increased Leukotriene Production and Reduced Lung Function and Asthma Control in Children with Poorly Controlled Asthma 
Background
Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy but its impact on disease control remains unclear.
Objective
We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score.
Methods
We analyzed 270 children 6-17 years old with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels.
Results
14.8% (40/270) of all children (and 28% (38/135) of African Americans) carried 2 non-5 repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 versus 30 nmol/mol creatinine, p=.0134), significantly worse FEV1% predicted (84 versus 91, p=.017), and a trend toward worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (r = -0.192, p=.009).
Conclusion and Clinical Relevance
Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function, and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.
doi:10.1111/cea.12076
PMCID: PMC3633142  PMID: 23600541
Asthma; Children; ALOX5; 5-Lipoxygenase; Leukotriene; Asthma Control; FEV1; Exhaled Nitric Oxide; Genetic Association
21.  A Cross Sectional Analysis of the Role of the Antimicrobial Peptide Cathelicidin in Lung Function Impairment within the ALIVE Cohort 
PLoS ONE  2014;9(4):e95099.
Background
Vitamin D deficiency is associated with reduced lung function. Cathelicidin, an antimicrobial peptide regulated by vitamin D, plays a role within the innate immune system. The association of cathelicidin with lung function decrement and respiratory infection is undefined.
We determined the independent relationship of cathelicidin with lung function.
Methods
In a cross-sectional analysis of 650 participants in an urban observational cohort with high smoking prevalence, plasma 25(OH)-vitamin D and cathelicidin levels were measured from stored samples obtained within 6 months of spirometry study visits. Multivariable linear regression was used to determine the independent association between low cathelicidin (defined as the lowest quartile of the cohort) and absolute forced expiratory volume in 1 second (FEV1).
Results
The mean age of the cohort was 49 years; 91% were black, 35% female and 41% HIV-infected. Participants with low cathelicidin had a 183 mL lower FEV1 compared to higher cathelicidin (p = 0.009); this relationship was maintained (115 ml lower; p = 0.035) after adjusting for demographics, BMI, and smoking. Neither HIV serostatus, heavy smoking history, nor 25(OH)-vitamin D levels were associated with cathelicidin levels. Participants with low cathelicidin had a greater prevalence of prior bacterial pneumonia (21% versus 14%; p = 0.047). Inclusion of pneumonia in adjusted models did not substantially reduce the FEV1 decrement observed with low cathelicidin (104 mL lower FEV1; p = 0.05). Lung function decrements associated with low cathelicidin were greatest among individuals with lower 25(OH)-vitamin D levels.
Conclusions
In a cohort at risk for airflow obstruction, low cathelicidin was independently associated with lower FEV1. These clinical data support a mechanistic link between 25(OH)-vitamin D deficiency and lung function impairment, independent of pneumonia risk.
doi:10.1371/journal.pone.0095099
PMCID: PMC3990590  PMID: 24743155
23.  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
24.  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
25.  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

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