Correspondence and requests for reprints should be addressed to Donata Vercelli, M.D., Graduate Program in Cellular and Molecular Medicine, Arizona Respiratory Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721. E-mail: donata@email.arizona.edu Ann Am Thorac Soc Vol 13, Supplement 1, p S99, Mar 2016 Copyright © 2016 by the American Thoracic Society Internet address: www.atsjournals.org DNA Methylation Changes in Nasal Epithelia Are Associated with Allergic Asthma in the Inner City Ivana V. Yang, Brent S. Pedersen, Andrew H. Liu, George T. O’Connor, Stephen J. Teach, Meyer Kattan, Rana T. Misiak, Rebecca Gruchalla, Suzanne F. Steinbach, Stanley J. Szefler, Michelle A. Gill, Agustin Calatroni, Gloria David, Corinne E. Hennessy, Elizabeth J. Davidson, Peter Gergen, Alkis Togias, William W. Busse, and David A. Schwartz University of Colorado School of Medicine, Aurora, Colorado; National Jewish Health, Denver, Colorado; Boston Abstracts S99 ABSTRACTSs S99 ABSTRACTS

Background: Epigenetic marks are heritable, influenced by the environment, direct the maturation of T lymphocytes, and in mice enhance the development of allergic airway disease. Thus it is important to define epigenetic alterations in asthmatic populations. Objective: We hypothesize that epigenetic alterations in circulating PBMCs are associated with allergic asthma.Methods: We compared DNA methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy control subjects by using DNA and RNA from PBMCs. Results were validated in an independent population of asthmatic patients.Results: Comparing asthmatic patients (n = 97) with control subjects (n = 97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL13, RUNX3, and specific genes relevant to T lymphocytes (TIGIT). Among asthmatic patients, 11 differentially methylated regions were associated with higher serum IgE concentrations, and 16 were associated with percent predicted FEV1. Hypomethylated and hypermethylated regions were associated with increased and decreased gene expression, respectively (P < 6 x 10(-12) for asthma and P < .01 for IgE). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma (IL4 and ST2). Methylation marks involved in T-cell maturation (RUNX3), T(H)2 immunity (IL4), and oxidative stress (catalase) were validated in an independent asthmatic cohort of children living in the inner city.Conclusions: Our results demonstrate that DNA methylation marks in specific gene loci are associated with asthma and suggest that epigenetic changes might play a role in establishing the immune phenotype associated with asthma.

Asthma in the US is widespread, with incidence rates and morbidity increasing dramatically over the last 2 decades. The cost of asthma-related morbidity and mortality is large. There is substantial and convincing evidence that environmental factors are associated with asthma exacerbation, and more limited evidence that environmental factors play a role in the development of asthma. Educational interventions, which include an avoidance of 'triggers' or focus on reducing exposure to cigarette smoke, have been shown to be moderately effective. While various interventions have been shown to reduce environmental exposures, fewer studies have collected sufficient information on their effectiveness in reducing morbidity.Cost-effectiveness analyses on educational interventions suggest that reductions in direct costs are most prominently seen for severe asthma, with the interpretation of study findings impaired by a lack of methodological consistency. One analysis from a study that included physical interventions found that the incremental cost-effectiveness ratio was $US9.20 per symptom-free day (95% CI-$US12.56, $US55.29), with potential cost savings for more severe asthma.We point out that current practice in managed care organizations (MCOs), as well as in other settings, rarely conforms to the current clinical practice guidelines for asthma. Two reviews of the policies and actions of MCOs found that while some were integrating environmental controls into their asthma disease management plans, their commitment to these strategies was limited by lack of a strong evidence base. We recommend the following: (i) continuation of educational programs; (ii) continuation and expansion of case management, including home visits; (iii) full integration of smoking cessation programs into asthma disease management; (iv) development of policies around reimbursement for durable goods; (v) participation in the setting of a policy agenda for population-based approaches to controlling key environmental factors; (vi) development of exploratory programs to address occupational asthma; (vii) integration, analysis and dissemination of environmental data collected by MCOs; and (viii) widespread MCO participation in research on environmental prevention of asthma.

BACKGROUNDResearch has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control.METHODSWe enrolled inner-city children, adolescents, and young adults with persistent asthma in a randomized, double-blind, placebo-controlled, parallel-group trial at multiple centers to assess the effectiveness of omalizumab, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma.RESULTSAmong 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists.CONCLUSIONSWhen added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; ClinicalTrials.gov number, NCT00377572.).

Background: There is an association between adiposity and asthma prevalence, but the relationship to asthma control is unclear.Objectives: We sought to understand the relationships among adiposity, sex, and asthma control in inner-city adolescents with asthma.Methods: We prospectively followed 368 adolescents with moderate-to-severe asthma (ages 12-20 years) living in 10 urban areas for 1 year. Asthma symptoms and exacerbations were recorded, and pulmonary function and exhaled nitric oxide levels were measured every 6 weeks. Adiposity measures (body mass index [BMI] and dual-energy X-ray absorptiometric scans) were made, and blood was collected for measurement of allergy markers, adiponectin, leptin, TNF-alpha, IL-6, and C-reactive protein levels.Results: More than 60% of female subjects and 50% of male subjects were above the 85th percentile of BMI for age. Higher BMI was associated with more symptom days (R = 0.18, P = .02) and exacerbations (R = 0.18, P = .06) among female subjects only. Adiponectin was inversely related to asthma symptoms (R = 0.18, P < .05) and exacerbations (R = 0.20, P < .05) and positively with FEN/1/forced vital capacity ratio (R = 0.15, P < .05) in male subjects only independent of body size. There was no relationship between adiposity or adipokines and total IgE levels, blood eosinophil counts, and exhaled nitric oxide levels. Dual-energy X-ray absorptiometry provided little additional value in relating adiposity to asthma outcome in this population of adolescents.Conclusion: Adiposity is associated with poorer asthma control in female subjects. Adiponectin is associated with improved asthma control in male subjects. (J Allergy Clin Immunol 2010;125:584-92.)

Background: With the expanding effort to provide guidelines-based therapy to adolescents with asthma, attention must be directed to evaluating which factors predict future asthma control when guidelines-based management is applied.Objective: We evaluated the role of fraction of exhaled nitric oxide in parts per billion, markers of allergic sensitization, airway inflammation, and measures of asthma severity in determining future risk of asthma symptoms and exacerbations in adolescents and young adults participating in the Asthma Control Evaluation study.Methods: Five hundred forty-six inner-city residents, ages 12 through 20 years, with persistent asthma were extensively evaluated at study entry for predictors of future symptoms and exacerbations over the subsequent 46 weeks, during which guidelines-based, optimal asthma management was offered. Baseline measurements included fraction of exhaled nitric oxide in parts per billion, total IgE, allergen-specific IgE, allergen skin test reactivity, asthma symptoms, lung function, peripheral blood eosinophils, and, for a subset, airway hyperresponsiveness and sputum eosinophils.Results: The baseline characteristics we examined accounted for only a small portion of the variance for future maximum symptom days and exacerbations-11.4% and 12.6%, respectively. Future exacerbations were somewhat predicted by asthma symptoms, albuterol use, previous exacerbations, and lung function, whereas maximum symptom days were predicted, also to a modest extent, by symptoms, albuterol use, and previous exacerbations, but not lung function.Conclusion: Our findings demonstrate that the usual predictors of future disease activity have little predictive power when applied to a highly adherent population with persistent asthma that is receiving guidelines-based care. Thus, new predictors need to be identified that will be able to measure the continued fluctuation of disease that persists in highly adherent, well-treated populations such as the one studied. (J Allergy Clin Immunol 2009;124:213-21.)

CONTEXT. Barriers impede translating recommendations for asthma treatment into practice, particularly in inner cities where asthma morbidity is highest. METHODS. The purpose of this study was to test the effectiveness of timely patient feedback in the form of a letter providing recent patient-specific symptoms, medication, and health service use combined with guideline-based recommendations for changes in therapy on improving the quality of asthma care by inner-city primary care providers and on resultant asthma morbidity. This was a randomized, controlled clinical trial in 5- to 11-year-old children (n = 937) with moderate to severe asthma receiving health care in hospital- and community-based clinics and private practices in 7 inner-city urban areas. The caretaker of each child received a bimonthly telephone call to collect clinical information about the child's asthma. For a full year, the providers of intervention group children received bimonthly computer-generated letters based on these calls summarizing the child's asthma symptoms, health service use, and medication use with a corresponding recommendation to step up or step down medications. We measured the number and proportion of scheduled visits resulting in stepping up of medications, asthma symptoms (2-week recall), and health care use (2-month recall). RESULTS. In this population, only a modest proportion of children whose symptoms warranted a medication increase actually had a scheduled visit to reevaluate their asthma treatment. However, in the 2-month interval after receipt of a step-up letter, 17.1% of the letters were followed by scheduled visits in the intervention group compared with scheduled visits 12.3% of the time by the control children with comparable clinical symptoms. Asthma medications were stepped up when indicated after 46.0% of these visits in the intervention group compared with 35.6% in the control group, and when asthma symptoms warranted a step up in therapy, medication changes occurred earlier among the intervention children. Among children whose medications were stepped up at any time during the 12-month study period, those in the intervention group experienced 22.1% fewer symptom days and 37.9% fewer school days missed. The intention-to-treat analysis showed no difference over the intervention year in the number of symptom days, yet there was a trend toward fewer days of limited activity and a significant decrease in emergency department visits by the intervention group compared with controls. This 24% drop in emergency department visits resulted in an intervention that was cost saving in its first year. CONCLUSIONS. Patient-specific feedback to inner-city providers increased scheduled asthma visits, increased asthma visits in which medications were stepped up when clinically indicated, and reduced emergency department visits.

Abstract Background Children in urban public housing are at high risk for asthma, given elevated environmental and social exposures and suboptimal medical care. For a multifactorial disease like asthma, design of intervention studies can be influenced by the relative prevalence of key risk factors. To better understand risk factors for asthma morbidity in the context of an environmental intervention study, we conducted a detailed baseline evaluation of 78 children (aged 4–17 years) from three public housing developments in Boston. Methods Asthmatic children and their caregivers were recruited between April 2002 and January 2003. We conducted intake interviews that captured a detailed family and medical history, including questions regarding asthma symptom severity, access to health care, medication usage, and psychological stress. Quality of life was evaluated for both the child and caregiver with an asthma-specific scale. Pulmonary function was measured with a portable spirometer, and allergy testing for common indoor and outdoor allergens was conducted with skin testing using the prick puncture method. Exploratory linear and logistic regression models evaluating predictors of respiratory symptoms, quality of life, and pulmonary function were conducted using SAS. Results We found high rates of obesity (56%) and allergies to indoor contaminants such as cockroaches (59%) and dust mites (59%). Only 36% of children with persistent asthma reported being prescribed any daily controller medication, and most did not have an asthma action plan or a peak flow meter. One-time lung function measures were poorly correlated with respiratory symptoms or quality of life, which were significantly correlated with each other. In multivariate regression models, household size, body mass index, and environmental tobacco smoke exposure were positively associated with respiratory symptom severity (p < 0.10). Symptom severity was negatively associated with asthma-related quality of life for the child and the caregiver, with caregiver (but not child) quality of life significantly influenced by caregiver stress and whether the child was in the intensive care unit at birth. Conclusion Given the elevated prevalence of multiple risk factors, coordinated improvements in the social environment, the built environment, and in medical management would likely yield the greatest health benefits in this high-risk population.