Environmental management of asthma in clinical practice: Results from the 2012 National Ambulatory Medical Care Survey.

Background: The National Asthma Education and Prevention Program guidelines emphasize environmental control as an integral part of asthma management; however, limited national-level data exist on how clinicians implement environmental control recommendations. Objective: We analyzed data on clinicians' self-reported use of recommended environmental control practices in a nationally representative sample (n = 1645) of primary care physicians, asthma specialists, and advanced practice providers from the National Asthma Survey of Physicians, a supplemental questionnaire to the 2012 National Ambulatory Medical Care Survey. Methods: We examined clinician and practice characteristics as well as clinicians' decisions and strategies regarding environmental trigger assessment and environmental control across provider groups. Regression modeling was used to identify clinician and practice characteristics associated with implementation of guideline recommendations. Results: A higher percentage of specialists assessed asthma triggers at home, school, and/or work than primary care or advanced practice providers (almost always: 53.6% vs 29.4% and 23.7%, respectively, P < .001). Almost all clinicians (>93%) recommended avoidance of secondhand tobacco smoke, whereas recommendations regarding cooking appliances (eg, proper ventilation) were infrequent. Although assessment and recommendation practices differed between clinician groups, modeling results showed that clinicians who reported almost always assessing asthma control were 5- to 6-fold more likely to assess environmental asthma triggers. Use of asthma action plans was also strongly associated with implementation of environmental control recommendations. Conclusions: Environmental assessment and recommendations to patients varied among asthma care providers. High adherence to other key guideline components, such as assessing asthma control, was associated with environmental assessment and recommendation practices on environmental control.

Clinical Phenotypes of Atopy and Asthma in COPD: A Meta-analysis of SPIROMICS and COPDGene.

BACKGROUND: Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies. RESEARCH QUESTION: What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)? STUDY DESIGN AND METHODS: Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis. RESULTS: The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes. INTERPRETATION: Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.

In-Home Secondhand Smoke Exposure Among Urban Children With Asthma: Contrasting Households With and Without Residential Smokers.

CONTEXT: Secondhand smoke exposure (SHSe) affects up to half of all children in the United States. Many studies have identified factors associated with in-home SHSe, but few have contrasted these factors between households with and without residential smokers. In the latter case, exposure occurs from only external sources that enter the home, such as visitors or environmental incursion. OBJECTIVE: Among children with SHSe at home, to examine demographic and psychosocial differences between households with and without residential smokers. DESIGN: Baseline analysis of an observational cohort. SETTING: Baltimore City, Maryland. PARTICIPANTS: A total of 157 children with asthma, aged 5 to 12 years. MEASURES: At-home airborne nicotine, caregiver-reported depression, asthma-related quality of life, functional social support, and demographics. Univariable comparisons were performed between SHS-exposed households with and without residential smokers. Multivariable logistic regression models were fit to examine associations between measured factors and absence of residential smokers. RESULTS: Children (78.3%) had at-home SHSe. Of these, 40.7% lived in households without residential smokers. Compared with households with residential smokers, these caregivers endorsed stronger beliefs in SHS harms and also worse functional social support and asthma-related stress, despite no differences in asthma morbidity. In adjusted models, SHS-exposed children with caregivers in the lowest tertile of functional social support (adjusted odds ratio, 3.50; 95% confidence interval, 1.12-10.99), asthma-related quality of life (2.90; 1.06-7.95), and those living alone (5.28; 1.26-22.15) had at least twice higher odds of having exclusively external SHSe than the highest tertile (P trends < .05). CONCLUSIONS: In-home SHS exposure remains alarmingly high in urban environments. However, a substantial proportion of this exposure appears to be occurring only from external sources that enter the home. Caregivers in these homes had higher desire but lower agency to avoid SHSe, driven by lack of functional support and physical isolation. Public policies targeting these factors may help remediate exposure in this especially vulnerable population.

Diet Pattern and Respiratory Morbidity in the Atherosclerosis Risk in Communities Study.

RATIONALE: Dietary intake is a potential risk factor for respiratory morbidity in adult populations. Few studies capture the effect of dietary patterns, representative of the combination of nutrients consumed, on self-reported respiratory morbidity in combination with objective measures of lung function. OBJECTIVES: To evaluate patterns of dietary intake in relation to respiratory morbidity and objective measures of lung function in a U.S. METHODS: The ARIC (Atherosclerosis Risk in Communities) study investigators enrolled 15,792 participants from four U.S. communities between 1987 and 1989 and collected data using a validated food frequency questionnaire to assess diet. Principal component analysis was applied, and patterns representative of "Western" and "Prudent" diets emerged. We investigated cross-sectional associations between dietary patterns and pulmonary assessments that included asthma and chronic obstructive pulmonary disease (COPD) diagnosis, respiratory symptoms, and lung function. Multivariable Poisson regression models included quintiles of dietary patterns and potential confounders. Interaction of dietary patterns with obesity, sex, and smoking status was assessed in relation to all outcomes. RESULTS: Higher scores in the "Western" dietary pattern (quintile 5 vs. quintile 1) were associated with higher prevalence of COPD (prevalence ratio [PR], 1.62; 95% confidence ratio [CI], 1.33-1.97), wheeze (PR, 1.37; 95% CI, 1.11-1.69), cough (PR, 1.32; 95% CI, 1.32-1.59), and phlegm (PR, 1.27; 95% CI, 1.05-1.54) and lower percent predicted forced expiratory volume in 1 second (FEV1), percent predicted forced vital capacity (FVC), and FEV1/FVC ratio. Higher scores in the "Prudent" dietary pattern (quintile 5 vs. quintile 1) were associated with lower prevalence of COPD (PR, 0.82; 95% CI, 0.70-0.95) and cough (PR, 0.77; 95% CI, 0.67-0.89) and higher percent predicted FEV1 and FEV1/FVC ratio. The prevalence of asthma was not related to dietary intake. CONCLUSIONS: A "Western" dietary pattern was associated with respiratory symptoms, lower lung function, and COPD in ARIC participants.

The feasibility of an air purifier and secondhand smoke education intervention in homes of inner city pregnant women and infants living with a smoker.

OBJECTIVES: Secondhand smoke (SHS) and other air pollutants adversely affect the health of pregnant women and infants. A feasibility study aimed at reducing air pollution in homes of pregnant women or infants living with a smoker was completed. METHODS: In collaboration with the Baltimore City Health Department, women ≥ 18 years of age and either pregnant nonsmokers, or post-partum (any smoking status) with an infant age 0-12 months were recruited. Homes had at least one smoker. Intervention included two air purifiers and secondhand smoke education. Outcomes included feasibility, change in fine particulate matter (PM2.5), air nicotine, and salivary cotinine pre- and post-intervention. RESULTS: Fifty women were enrolled (mean age 27 years, 92% African American, 71% single, 94% Medicaid eligible, 34% reported smoking) and 86% completed the study. Of the 50 women, 32 had infants and 18 were pregnant at time of enrollment. Post- intervention, 70% of participants reported smokers were less likely to smoke indoors, and 77% had at least one air purifier turned on at the final visit. Participant satisfaction was high (91%) and 98% would recommend air purifiers. Indoor PM2.5 was significantly decreased (P < 0.001). Salivary cotinine was significantly decreased for non-smoking women (P < 0.01) but not infants, and no significant change in air nicotine occurred (P = 0.6). CONCLUSIONS: Air purifiers with SHS education is a feasible intervention in homes of women and infants. These data demonstrate reduction in indoor PM2.5 and salivary cotinine in non-smoking adults. Air purifiers are not an alternative for smoking cessation and a home/ car smoking ban. Smoking cessation should be strongly encouraged for all pregnant women, and nonsmoking mothers with infants should be counseled to completely avoid SHS exposure. This study provides support for a future intervention evaluating clinical endpoints.

Predictors of polycyclic aromatic hydrocarbon exposure and internal dose in inner city Baltimore children.

Polycyclic aromatic hydrocarbons (PAHs), the by-products of incomplete combustion of organic materials, are commonly found on particulate matter (PM) and have been associated with the development of asthma and asthma exacerbation in urban populations. We examined time spent in the home and outdoors as predictors of exposures to airborne PAHs and measured urinary 1-hydroxypyrene-glucuronide (1-OHPG) as internal dose of PAHs in 118 children aged 5-12 years from Baltimore, MD. During weeklong periods (Saturday-Saturday) in each of four seasons: daily activities were assessed using questionnaires, indoor air nicotine and PM concentrations were monitored, and urine specimens were collected on Tuesday (day 3) and Saturday (day 7) for measurement of 1-OHPG. Time spent in non-smoking homes was associated with significantly decreased 1-OHPG concentration in urine (ß=-0.045, 95% CI (-0.076, -0.013)), and secondhand smoke (SHS) exposures modified these associations, with higher urinary 1-OHPG concentrations in children spending time in smoking homes than non-smoking homes (P-value for interaction=0.012). Time spent outdoors was associated with increased urinary 1-OHPG concentrations (ß=0.097, 95% CI (0.037, 0.157)) in boys only. Our results suggest that SHS and ambient (outdoor) air pollution contribute to internal dose of PAHs in inner city children.

A Randomized Controlled Trial of the Effect of Broccoli Sprouts on Antioxidant Gene Expression and Airway Inflammation in Asthmatics.

BACKGROUND: Broccoli sprouts (BS) are the richest source of sulforaphane (SFN), which is a potent inducer of phase II enzymes, which play a critical role in preventing oxidative stress (OS) and inflammation. OBJECTIVES: The objective of this study was to determine if ingestion of whole BS improves airway inflammatory and physiologic outcomes, and OS in adults with asthma and allergic sensitization to an indoor allergen. METHODS: The study is a double-blind, placebo-controlled, randomized trial to compare the effects of BS with placebo (alfalfa sprouts [AS]) on airway inflammation and markers of OS. Forty adults (aged 18-50 years) were randomized to eat either (a) 100 g of BS daily or (b) 100 g of AS daily for 3 days. Fractional exhaled nitric oxide (FENO), forced expiratory volume 1, nasal epithelial and PBMC gene expression, inflammatory and OS biomarkers, and symptoms were assessed both before and after ingestion of the sprouts. The primary outcome variable was the change in FENO. Secondary outcome measures included rhinitis and asthma symptoms, lung function, and OS and inflammatory biomarkers. RESULTS: BS ingestion for 3 consecutive days did not reduce FENO, despite resulting in a marked increase in serum SFN concentrations (21 vs 22 parts per billion, P = .76). Furthermore, BS consumption did not induce cytoprotective antioxidant genes in either PBMCs or nasal epithelial cells, reduce OS and inflammatory markers, or improve lung function. CONCLUSIONS: Ingestion of whole BS for 3 days does not appear to improve eosinophilic pulmonary inflammation, inflammatory and OS biomarkers, or clinical features of asthma among atopic adults with asthma despite resulting in a marked increase in serum SFN levels.

Urbanization and Daily Exposure to Biomass Fuel Smoke Both Contribute to Chronic Bronchitis Risk in a Population with Low Prevalence of Daily Tobacco Smoking.

OBJECTIVE: Risk factors beyond tobacco smoking associated with chronic bronchitis are not well understood. We sought to describe the prevalence and risk factors of chronic bronchitis across four distinct settings in Peru with overall low prevalence of tobacco smoking yet varying degrees of urbanization, daily exposure to biomass fuel smoke and living at high altitude. METHODS: We analyzed data of 2,947 participants from rural and urban Puno, Lima and Tumbes including spirometry, blood samples, anthropometry and administered questionnaires about respiratory symptoms. We used multivariable Poisson regression to assess biologic, socioeconomic and environmental risk factors associated with chronic bronchitis. RESULTS: Overall prevalence of chronic bronchitis was 5.9% (95%CI 5.1%-6.9%) with variation by setting: prevalence was lower in semi-urban Tumbes (1.3%) vs. highly urbanized Lima (8.9%), urban Puno (7.0%) and rural Puno (7.8%; p < 0.001). Chronic bronchitis was more common among participants with vs. without COPD based on FEV1/FVC< LLN (12.1% vs 5.6%, p < 0.01) and it was associated with increased reporting of dyspnea on exertion (p < 0.001), hospitalization (p = 0.003) and workdays missed due to respiratory symptoms (p < 0.001). Older age (Prevalence ratio [PR] = 1.23 for each 10-years of age, 95%CI 1.09-1.40) past history of asthma (PR = 2.87, 95%CI 1.80-4.56), urbanization (PR = 3.34, 95%CI 2.18-5.11) and daily exposure to biomass fuel smoke (PR = 2.00, 95%CI 1.30-3.07) were all associated with chronic bronchitis. CONCLUSIONS: We found important variations in the prevalence of chronic bronchitis across settings. Prevalence increased with both urbanization and with daily exposure to biomass fuel smoke. Having chronic bronchitis was also associated with worse patient-centered outcomes including dyspnea, hospitalization and missed workdays.

Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function.

Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47-59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2'-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.

Prevalence of chronic obstructive pulmonary disease and variation in risk factors across four geographically diverse resource-limited settings in Peru.

BACKGROUND: It is unclear how geographic and social diversity affects the prevalence of chronic obstructive pulmonary disease (COPD). We sought to characterize the prevalence of COPD and identify risk factors across four settings in Peru with varying degrees of urbanization, altitude, and biomass fuel use. METHODS: We collected sociodemographics, clinical history, and post-bronchodilator spirometry in a randomly selected, age-, sex- and site-stratified, population-based sample of 2,957 adults aged ≥35 years (median age was 54.8 years and 49.3% were men) from four resource-poor settings: Lima, Tumbes, urban and rural Puno. We defined COPD as a post-bronchodilator FEV1/FVC < 70%. RESULTS: Overall prevalence of COPD was 6.0% (95% CI 5.1%-6.8%) but with marked variation across sites: 3.6% in semi-urban Tumbes, 6.1% in urban Puno, 6.2% in Lima, and 9.9% in rural Puno (p < 0.001). Population attributable risks (PARs) of COPD due to smoking ≥10 pack-years were less than 10% for all sites, consistent with a low prevalence of daily smoking (3.3%). Rather, we found that PARs of COPD varied by setting. In Lima, for example, the highest PARs were attributed to post-treatment tuberculosis (16% and 22% for men and women, respectively). In rural Puno, daily biomass fuel for cooking among women was associated with COPD (prevalence ratio 2.22, 95% CI 1.02-4.81) and the PAR of COPD due to daily exposure to biomass fuel smoke was 55%. CONCLUSIONS: The burden of COPD in Peru was not uniform and, unlike other settings, was not predominantly explained by tobacco smoking. This study emphasizes the role of biomass fuel use, and highlights pulmonary tuberculosis as an often neglected risk factor in endemic areas.

Occupational exposures are associated with worse morbidity in patients with chronic obstructive pulmonary disease.

RATIONALE: Links between occupational exposures and morbidity in individuals with established chronic obstructive pulmonary disease (COPD) remain unclear. OBJECTIVES: To determine the impact of occupational exposures on COPD morbidity. METHODS: A job exposure matrix (JEM) determined occupational exposure likelihood based on longest job in current/former smokers (n = 1,075) recruited as part of the Subpopulations and Intermediate Outcomes in COPD Study, of whom 721 had established COPD. Bivariate and multivariate linear regression models estimated the association of occupational exposure with COPD, and among those with established disease, the occupational exposure associations with 6-minute-walk distance (6MWD), the Modified Medical Research Council Dyspnea Scale (mMRC), the COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), 12-item Short-Form Physical Component (SF-12), and COPD exacerbations requiring health care utilization, adjusting for demographics, current smoking status, and cumulative pack-years. MEASUREMENTS AND MAIN RESULTS: An intermediate/high risk of occupational exposure by JEM was found in 38% of participants. In multivariate analysis, those with job exposures had higher odds of COPD (odds ratio, 1.44; 95% confidence interval, 1.04-1.97). Among those with COPD, job exposures were associated with shorter 6MWDs (-26.0 m; P = 0.006); worse scores for mMRC (0.23; P = 0.004), CAT (1.8; P = 0.003), SGRQ (4.5; P = 0.003), and SF-12 Physical (-3.3; P < 0.0001); and greater odds of exacerbation requiring health care utilization (odds ratio, 1.55; P = 0.03). CONCLUSIONS: Accounting for smoking, occupational exposure was associated with COPD risk and, for those with established disease, shorter walk distance, greater breathlessness, worse quality of life, and increased exacerbation risk. Clinicians should obtain occupational histories from patients with COPD because work-related exposures may influence disease burden.

Obesity as a susceptibility factor to indoor particulate matter health effects in COPD.

Our goal was to investigate whether obesity increases susceptibility to the adverse effects of indoor particulate matter on respiratory morbidity among individuals with chronic obstructive pulmonary disease (COPD). Participants with COPD were studied at baseline, 3 and 6 months. Obesity was defined as a body mass index ≥30 kg·m(-2). At each time point, indoor air was sampled for 5-7 days and particulate matter (PM) with an aerodynamic size ≤2.5 µm (PM2.5) and 2.5-10 µm (PM2.5-10) was measured. Respiratory symptoms, health status, rescue medication use, exacerbations, blood biomarkers and exhaled nitric oxide were assessed simultaneously. Of the 84 participants enrolled, 56% were obese and all were former smokers with moderate-to-severe COPD. Obese participants tended to have less severe disease as assessed by Global Initiative for Chronic Obstructive Pulmonary Disease stage and fewer pack-years of smoking. There was evidence that obesity modified the effects of indoor PM on COPD respiratory outcomes. Increases in PM2.5 and PM2.5-10 were associated with greater increases in nocturnal symptoms, dyspnoea and rescue medication use among obese versus non-obese participants. The impact of indoor PM on exacerbations, respiratory status and wheeze also tended to be greater among obese versus non-obese participants, as were differences in airway and systemic inflammatory responses to indoor PM. We found evidence that obesity was associated with exaggerated responses to indoor fine and coarse PM exposure among individuals with COPD.

Factors that influence physician decision making for indeterminate pulmonary nodules.

RATIONALE: Pulmonologists frequently encounter indeterminate pulmonary nodules in practice, but it is unclear what clinical factors they rely on to guide the diagnostic evaluation. OBJECTIVES: To assess the current approach to the management of indeterminate pulmonary nodules and to determine the extent to which the addition of a hypothetical diagnostic blood test will influence clinical decision making. METHODS: Selected pulmonologists practicing in the United States were invited to participate in a conjoint exercise based on 20 randomly generated cases of varying age, smoking history, and nodule size. Some cases included the result of a hypothetical blood test. Each respondent chose from among three diagnostic options for a patient: noninvasive monitoring (i.e., serial CT or positron emission tomography scan), a minor procedure (i.e., biopsy or bronchoscopy), or a major procedure (i.e., video-assisted thorascopic surgery or thoracotomy). Multivariate logistic regression was used to assess the impact of the three risk factors and the diagnostic blood test on decision making. MEASUREMENTS AND MAIN RESULTS: Four hundred nineteen physicians participated (response rate, 10%). One hundred fifty-three physician surveys met predetermined criteria and were analyzed (4% of all invitees). A diagnostic procedure was recommended for 23% of 6-mm nodules, versus 54, 66, 77, and 84% of nodules 10, 14, 18, and 22 mm, respectively (P < 0.001). Older age limited recommendations for invasive testing: 54% of 80-year-olds versus 61, 64, 63, and 61% of patients 71, 62, 53, and 44 years of age, respectively (P < 0.001). In multivariate analyses, nodule size, smoking history, age, and the blood test each influenced decision making (P < 0.001). CONCLUSIONS: The pulmonologists who participated in this survey were more likely to proceed with invasive testing, instead of observation or additional imaging, as the size of the nodule increased. The use of a hypothetical blood test resulted in significant alterations in the decision to pursue invasive testing.

Indoor pollutant exposure is associated with heightened respiratory symptoms in atopic compared to non-atopic individuals with COPD.

BACKGROUND: Indoor particulate matter (PM) has been linked to respiratory symptoms in former smokers with COPD. While subjects with COPD and atopy have also been shown to have more frequent respiratory symptoms, whether they exhibit increased susceptibility to PM as compared to their non-atopic counterparts remains unclear. The aim of this study was to determine whether atopic individuals with COPD have greater susceptibility to PM compared to non-atopic individuals with COPD. METHODS: Former smokers with moderate to severe COPD were enrolled (n = 77). PM2.5, PM with diameter <2.5 micrometers, was measured in the main living area over three one-week monitoring periods at baseline, 3, and 6 months. Quality of life, respiratory symptoms and medication use were assessed by questionnaires. Serum was analyzed for specific IgE for mouse, cockroach, cat, dog and dust mite allergens. Atopy was established if at least one test was positive. Interaction terms between PM and atopy were tested and generalized estimating equation analysis determined the effect of PM concentrations on health outcomes. Multivariate models were adjusted for age, sex, education, race, season, and baseline lung function and stratified by atopic status. RESULTS: Among atopic individuals, each 10 µg/m(3) increase in PM was associated with higher risk of nocturnal symptoms (OR, 1.95; P = 0.02), frequent wheezing (OR, 2.49; P = 0.02), increased rescue medication use (ß = 0.14; P = 0.02), dyspnea (ß = 0.23; P < 0.001), higher St. George's Respiratory Quality of Life score (ß = 2.55; P = 0.01), and higher breathlessness, cough, and sputum score (BCSS) (ß = 0.44; P = 0.01). There was no association between PM and health outcomes among the non-atopic individuals. Interaction terms between PM2.5 and atopy were statistically significant for nocturnal symptoms, frequency of rescue medication use, and BCSS (all P < 0.1). CONCLUSIONS: Individuals with COPD and atopy appear to be at higher risk of adverse respiratory health effects of PM exposure compared to non-atopic individuals with COPD.

A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes.

BACKGROUND: Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. OBJECTIVE: We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4(+) lymphocytes for association with asthma. METHODS: eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. RESULTS: Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10(-8)). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P = .002), N-acetyl-α-D-galactosaminidase (NAGA; P = .0002), and Factor XIII, A1 (F13A1; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4(+) lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. CONCLUSIONS: Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.

Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children.

RATIONALE: The effect of endotoxin on asthma morbidity in urban populations is unclear. OBJECTIVES: To determine if indoor pollutant exposure modifies the relationships between indoor airborne endotoxin and asthma health and morbidity. METHODS: One hundred forty-six children and adolescents with persistent asthma underwent repeated clinical assessments at 0, 3, 6, 9, and 12 months. Home visits were conducted at the same time points for assessment of airborne nicotine, endotoxin, and nitrogen dioxide (NO2) concentrations. The effect of concomitant pollutant exposure on relationships between endotoxin and asthma outcomes were examined in stratified analyses and statistical models with interaction terms. MEASUREMENTS AND MAIN RESULTS: Both air nicotine and NO2 concentrations modified the relationships between airborne endotoxin and asthma outcomes. Among children living in homes with no detectable air nicotine, higher endotoxin was inversely associated with acute visits and oral corticosteroid bursts, whereas among those in homes with detectable air nicotine, endotoxin was positively associated with these outcomes (interaction P value = 0.004 and 0.07, respectively). Among children living in homes with lower NO2 concentrations (<20 ppb), higher endotoxin was positively associated with acute visits, whereas among those living in homes with higher NO2 concentrations, endotoxin was negatively associated with acute visit (interaction P value = 0.05). NO2 also modified the effect of endotoxin on asthma symptom outcomes in a similar manner. CONCLUSIONS: The effects of household airborne endotoxin exposure on asthma are modified by coexposure to air nicotine and NO2, and these pollutants have opposite effects on the relationships between endotoxin and asthma-related outcomes.

Mouse allergen is the major allergen of public health relevance in Baltimore City.

BACKGROUND: Cockroach and mouse allergens have both been implicated as causes in inner-city asthma morbidity in multicenter studies, but whether both allergens are clinically relevant within specific inner-city communities is unclear. OBJECTIVE: Our study aimed to identify relevant allergens in Baltimore City. METHODS: One hundred forty-four children (5-17 years old) with asthma underwent skin prick tests at baseline and had clinical data collected at baseline and 3, 6, 9, and 12 months. Home settled dust samples were collected at the same time points for quantification of indoor allergens. Participants were grouped based on their sensitization and exposure status to each allergen. All analyses were adjusted for age, sex, and serum total IgE level. RESULTS: Forty-one percent were mouse sensitized/exposed, and 41% were cockroach sensitized/exposed based on bedroom floor exposure data. Mouse sensitization/exposure was associated with acute care visits, decreased FEV1/forced vital capacity percentage values, fraction of exhaled nitric oxide levels, and bronchodilator reversibility. Cockroach sensitization/exposure was only associated with acute care visits and bronchodilator reversibility when exposure was defined by using bedroom floor allergen levels. Mouse-specific IgE levels were associated with poor asthma health across a range of outcomes, whereas cockroach-specific IgE levels were not. The relationships between asthma outcomes and mouse allergen were independent of cockroach allergen. Although sensitization/exposure to both mouse and cockroach was generally associated with worse asthma, mouse sensitization/exposure was the primary contributor to these relationships. CONCLUSIONS: In a community with high levels of both mouse and cockroach allergens, mouse allergen appears to be more strongly and consistently associated with poor asthma outcomes than cockroach allergen. Community-level asthma interventions in Baltimore should prioritize reducing mouse allergen exposure.

Effects of allergic phenotype on respiratory symptoms and exacerbations in patients with chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) guidelines make no recommendations for allergy diagnosis or treatment. OBJECTIVES: To determine whether an allergic phenotype contributes to respiratory symptoms and exacerbations in patients with COPD. METHODS: Two separate cohorts were analyzed: National Health and Nutrition Survey III (NHANES III) and the COPD and domestic endotoxin (CODE) cohort. Subjects from NHANES III with COPD (n = 1,381) defined as age > 40 years, history of smoking, FEV1/FVC < 0.70, and no diagnosis of asthma were identified. The presence of an allergic phenotype (n = 296) was defined as self-reported doctor diagnosed hay fever or allergic upper respiratory symptoms. In CODE, former smokers with COPD (n = 77) were evaluated for allergic sensitization defined as a detectable specific IgE to perennial allergens. Bivariate and multivariate models were used to determine whether an allergic phenotype was associated with respiratory symptoms and exacerbations. MEASUREMENTS AND MAIN RESULTS: In NHANES III, multivariate analysis revealed that individuals with allergic phenotype were more likely to wheeze (odds ratio [OR], 2.1; P < 0.01), to have chronic cough (OR, 1.9; P = 0.01) and chronic phlegm (OR, 1.5; P < 0.05), and to have increased risk of COPD exacerbation requiring an acute doctor visit (OR, 1.7; P = 0.04). In the CODE cohort, multivariate analysis revealed that sensitized subjects reported more wheeze (OR, 5.91; P < 0.01), more nighttime awakening due to cough (OR, 4.20; P = 0.03), increased risk of COPD exacerbations requiring treatment with antibiotics (OR, 3.79; P = 0.02), and acute health visits (OR, 11.05; P < 0.01). An increasing number of sensitizations was associated with a higher risk for adverse health outcomes. CONCLUSIONS: Among individuals with COPD, evidence of an allergic phenotype is associated with increased respiratory symptoms and risk of COPD exacerbations.

In-home air pollution is linked to respiratory morbidity in former smokers with chronic obstructive pulmonary disease.

RATIONALE: The effect of indoor air pollutants on respiratory morbidity among patients with chronic obstructive pulmonary disease (COPD) in developed countries is uncertain. OBJECTIVES: The first longitudinal study to investigate the independent effects of indoor particulate matter (PM) and nitrogen dioxide (NO(2)) concentrations on COPD morbidity in a periurban community. METHODS: Former smokers with COPD were recruited and indoor air was monitored over a 1-week period in the participant's bedroom and main living area at baseline, 3 months, and 6 months. At each visit, participants completed spirometry and questionnaires assessing respiratory symptoms. Exacerbations were assessed by questionnaires administered at clinic visits and monthly telephone calls. MEASUREMENTS AND MAIN RESULTS: Participants (n = 84) had moderate or severe COPD with a mean FEV1 of 48.6% predicted. The mean (± SD) indoor PM(2.5) and NO(2) concentrations were 11.4 ± 13.3 µg/m(3) and 10.8 ± 10.6 ppb in the bedroom, and 12.2 ± 12.2 µg/m(3) and 12.2 ± 11.8 ppb in the main living area. Increases in PM(2.5) concentrations in the main living area were associated with increases in respiratory symptoms, rescue medication use, and risk of severe COPD exacerbations. Increases in NO(2) concentrations in the main living area were independently associated with worse dyspnea. Increases in bedroom NO(2) concentrations were associated with increases in nocturnal symptoms and risk of severe COPD exacerbations. CONCLUSIONS: Indoor pollutant exposure, including PM(2.5) and NO(2), was associated with increased respiratory symptoms and risk of COPD exacerbation. Future investigations should include intervention studies that optimize indoor air quality as a novel therapeutic approach to improving COPD health outcomes.