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2.  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
3.  Epithelial Nuclear Factor- kappa B orchestrates house dust mite-induced airway inflammation, hyperresponsiveness, and fibrotic remodeling 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(12):10.4049/jimmunol.1301329.
NF-κB activation within the epithelium has been implicated in the pathogenesis of asthma, yet the exact role of epithelial NF-κB in allergen-induced inflammation and airway remodeling remains unclear. In the present study, we utilized an intranasal House Dust Mite (HDM) extract exposure regimen time course in BALB/c mice to evaluate inflammation, NF-κB activation, airway hyperresponsiveness (AHR), and airway remodeling. We utilized CC10-IκBαSR transgenic mice to evaluate the functional importance of epithelial NF-κB in response to HDM. After a single exposure of HDM, mRNA expression of pro-inflammatory mediators was significantly elevated in lung tissue of WT mice, in association with increases in nuclear RelA and RelB, components of the classical and alternative NF-κB pathway, respectively, in the bronchiolar epithelium. In contrast, CC10-IκBαSR mice displayed marked decreases in nuclear RelA and RelB and mRNA expression of pro-inflammatory mediators compared to WT mice. After 15 challenges with HDM, WT mice exhibited increases in inflammation, airway hyperresponsiveness, mucus metaplasia and peri-bronchiolar fibrosis. CC10-IκBαSR transgenic mice displayed marked decreases in neutrophilic infiltration, tissue damping, and elastance parameters, in association will less peri-bronchiolar fibrosis and decreases in nuclear RelB in lung tissue. However, central airway resistance and mucus metaplasia remained elevated in CC10-IκBαSR transgenic mice, in association with continued presence of lymphocytes, and partial decreases in eosinophils and IL-13. The current study demonstrates that following airway exposure with an asthma-relevant allergen, activation of classical and alternative NF-κB pathways occur within the airway epithelium and may coordinately contribute to allergic inflammation, AHR and fibrotic airway remodeling.
doi:10.4049/jimmunol.1301329
PMCID: PMC3858534  PMID: 24227776
4.  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
5.  Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation 
Leukotrienes (i.e., products of the 5-lipoxygenase pathway) are thought to be contributors to lung pathologies. Moreover, eosinophils have been linked with pulmonary leukotriene activities both as potential sources of these mediators and as responding effector cells. The objective of the present study was to define the role(s) of leukotrienes in the lung pathologies accompanying eosinophil-associated chronic respiratory inflammation. A transgenic mouse model of chronic T helper (Th) 2–driven inflammation expressing IL-5 from T cells and human eotaxin-2 locally in the lung (I5/hE2) was used to define potential in vivo relationships among eosinophils, leukotrienes, and chronic Th2-polarized pulmonary inflammation. Airway levels of cys-leukotrienes and leukotriene B4 (LTB4) are both significantly elevated in I5/hE2 mice. The eosinophil-mediated airway hyperresponsiveness (AHR) characteristic of these mice was abolished in the absence of leukotrienes (i.e., 5-lipoxygenase–deficient I5/hE2). More importantly, the loss of leukotrienes led to an unexpectedly significant decrease in collagen deposition (i.e., pulmonary fibrosis) that accompanied elevated levels of IL-4/-13 and TGF-β in the lungs of I5/hE2 mice. Further studies using mice deficient for the LTB4 receptor (BLT-1−/−/I5/hE2) and I5/hE2 animals administered a cys-leukotriene receptor antagonist (montelukast) demonstrated that the AHR and the enhanced pulmonary fibrosis characteristic of the I5/hE2 model were uniquely cys-leukotriene–mediated events. These data demonstrate that, similar to allergen challenge models of wild-type mice, cys-leukotrienes underlie AHR in this transgenic model of severe pulmonary Th2 inflammation. These data also suggest that an underappreciated link exists among eosinophils, cys-leukotriene–mediated events, and fibrotic remodeling associated with elevated levels of IL-4/-13 and TGF-β.
doi:10.1165/rcmb.2013-0009OC
PMCID: PMC3931112  PMID: 23859654
5-lipoxygenase; asthma; eosinophils; montelukast; lung
6.  A genome-wide association study of bronchodilator response in asthmatics 
The pharmacogenomics journal  2013;14(1):41-47.
Reversibility of airway obstruction in response to β2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534,290 single nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215, and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (p=1.98×10−7) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (p=8.51×10−6). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.
doi:10.1038/tpj.2013.5
PMCID: PMC3706515  PMID: 23508266
pharmacogenetics; asthma; bronchodilator response; genome-wide association study; albuterol
7.  Polygenic Heritability Estimates in Pharmacogenetics: Focus on Asthma and Related Phenotypes 
Pharmacogenetics and genomics  2013;23(6):324-328.
While accurate measures of heritability are needed to understand the pharmacogenetic basis of drug treatment response, these are generally not available, since it is unfeasible to give medications to individuals for which treatment is not indicated. Using a polygenic linear mixed modeling approach, we estimated lower-bounds on asthma heritability and the heritability of two related drug-response phenotypes, bronchodilator response and airway hyperreactivity, using genome-wide SNP data from existing asthma cohorts. Our estimate of the heritability for bronchodilator response is 28.5% (se 16%, p = 0.043) and airway hyperresponsiveness is 51.1% (se 34%, p = 0.064), while we estimate asthma genetic liability at 61.5% (se 16%, p < 0.001). Our results agree with previously published estimates of the heritability of these traits, suggesting that the LMM method is useful for computing the heritability of other pharmacogenetic traits. Furthermore, our results indicate that multiple SNP main-effects, including SNPs as yet unidentified by GWAS methods, together explain a sizable portion of the heritability of these traits.
doi:10.1097/FPC.0b013e3283607acf
PMCID: PMC3767309  PMID: 23532052
Asthma; Pharmacogenetics; Heritability; Bronchodilator Response; Airway Hyperresponsiveness
9.  Endoplasmic reticulum stress mediates house dust mite-induced airway epithelial apoptosis and fibrosis 
Respiratory Research  2013;14(1):141.
Background
The endoplasmic reticulum (ER) stress response participates in many chronic inflammatory and autoimmune diseases. In the current study, we sought to examine the contribution of ER stress transducers in the pathogenesis of three principal facets of allergic asthma: inflammation, airway fibrosis, and airways hyperresponsiveness.
Methods
House Dust Mite (HDM) was used as an allergen for in vitro and in vivo challenge of primary human and murine airway epithelial cells. ER stress transducers were modulated using specific small interfering RNAs (siRNAs) in vivo. Inflammation, airway remodeling, and hyperresponsiveness were measured by total bronchoalveolar lavage (BAL) cell counts, determination of collagen, and methacholine responsiveness in mice, respectively.
Results
Challenge of human bronchiolar and nasal epithelial cells with HDM extract induced the ER stress transducer, activating transcription factor 6 α (ATF6α) as well as protein disulfide isomerase, ERp57, in association with activation of caspase-3. SiRNA-mediated knockdown of ATF6α and ERp57 during HDM administration in mice resulted in a decrease in components of HDM-induced ER stress, disulfide mediated oligomerization of Bak, and activation of caspase-3. Furthermore, siRNA-mediated knockdown of ATF6α and ERp57 led to decreased inflammation, airway hyperresponsiveness and airway fibrosis.
Conclusion
Collectively, our work indicates that HDM induces ER stress in airway epithelial cells and that ATF6α and ERp57 play a significant role in the development of cardinal features of allergic airways disease. Inhibition of ER stress responses may provide a potential therapeutic avenue in chronic asthma and sub-epithelial fibrosis associated with loss of lung function.
doi:10.1186/1465-9921-14-141
PMCID: PMC3877992  PMID: 24364984
Allergen; HDM; Unfolded protein response; ER stress; Apoptosis; Asthma; Airway fibrosis
10.  A polymorphism in the thyroid hormone receptor gene is associated with bronchodilator response in asthmatics 
The pharmacogenomics journal  2012;13(2):130-136.
A pro-asthmatic culture milieu and β2-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing p values < 0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5’ of the thyroid hormone receptor beta gene was associated with BDR in the childhood population and two adult populations (p value = 0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management.
doi:10.1038/tpj.2011.56
PMCID: PMC3349771  PMID: 22212731
Bronchodilator response; transcription factor; association; thyroid hormone receptor β; asthma; pharmacogenetics
11.  Obesity and Asthma 
Rationale: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese.
Objectives: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity.
Methods: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time.
Measurements and Main Results: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = −0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery.
Conclusions: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation.
doi:10.1164/rccm.201203-0573OC
PMCID: PMC3480522  PMID: 22837379
asthma; obesity; adipokine; airway hyperreactivity
12.  Physiologic Dysfunction of the Asthmatic Lung 
Asthma is a syndrome of lung dysfunction characterized by airflow obstruction, reversibility to bronchodilators, and airways hyperresponsiveness (AHR). There is a growing body of evidence that suggests that the principle defect in asthma is the occlusion of the airway lumen by liquid, fibrin, and mucus. The fall in FEV1 observed in asthma is best explained by a loss of communicating airspaces and the rise in residual lung volume. Imaging studies in both human patients and experimental animals support this hypothesis. An increased propensity for the airways to close can be a cause of AHR. We conclude that loss of lung volume plays a central role in determining the dysfunction of the asthmatic lung as measured by FEV1. Together, these recent findings provide a better understanding of the causes of airflow obstruction and AHR, suggesting new avenues for the development of more effective asthma therapies.
doi:10.1513/pats.200808-091RM
PMCID: PMC2677406  PMID: 19387035
lung volume; peripheral resistance; FEV1; airways hyperresponsiveness; airway closure
13.  Development of a Pharmacogenetic Predictive Test in asthma: proof of concept 
Pharmacogenetics and genomics  2010;20(2):86-93.
Objective
To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR).
Methods
We genotyped SNPs that tagged the whole genome of the parents and children in the Childhood Asthma Management Program (CAMP) and implemented an algorithm using a family-based association test that ranked SNPs by statistical power. The top eight SNPs that were associated with BDR comprised the Pharmacogenetic Predictive Test. The Clinical Predictive Test was comprised of baseline forced expiratory volume in 1 s (FEV1). We evaluated these predictive tests and a Combined Clinical and Pharmacogenetic Predictive Test in three distinct populations: the children of the CAMP trial and two additional clinical trial populations of asthma. Our outcome measure was poor BDR, defined as BDR of less than 20th percentile in each population. BDR was calculated as the percent difference between the prebronchodilator and postbronchodilator (two puffs of albuterol at 180 μg/puff) FEV1 value. To assess the predictive ability of the test, the corresponding area under the receiver operating characteristic curves (AUROCs) were calculated for each population.
Results
The AUROC values for the Clinical Predictive Test alone were not significantly different from 0.50, the AUROC of a random classifier. Our Combined Clinical and Pharmacogenetic Predictive Test comprised of genetic polymorphisms in addition to FEV1 predicted poor BDR with an AUROC of 0.65 in the CAMP children (n= 422) and 0.60 (n= 475) and 0.63 (n= 235) in the two independent populations. Both the Combined Clinical and Pharmacogenetic Predictive Test and the Pharmacogenetic Predictive Test were significantly more accurate than the Clinical Predictive Test (AUROC between 0.44 and 0.55) in each of the populations.
Conclusion
Our finding that genetic polymorphisms with a clinical trait are associated with BDR suggests that there is promise in using multiple genetic polymorphisms simultaneously to predict which asthmatics are likely to respond poorly to bronchodilators.
doi:10.1097/FPC.0b013e32833428d0
PMCID: PMC3654515  PMID: 20032818
asthma; bronchodilator response; personalized medicine; pharmacogenetic test; predictive medicine
14.  Airway Hyperresponsiveness and Inflammation: Causation, Correlation, or No Relation? 
Journal of allergy & therapy  2012;2012(Suppl 1):008.
Asthma represents a growing problem in the developing world, affecting millions of children and adults. Features of the disease are reversible airflow obstruction, airway hyperresponsiveness and airway inflammation leading to tissue damage and remodeling. Many studies have attempted to address whether inflammation and airway hyperresponsiveness are mechanistically linked. In this study, data are presented from several mouse models that illustrate that a clear link between these features of asthma remains elusive. The impact of altering inflammatory signaling (NF-κB or JNK1) on inflammation and airway hyperresponsiveness was examined. In addition, the effect of antigen sensitization and the route of antigen delivery were investigated. The data herein show that in many cases, inflammation and airway hyperresponsiveness do not directly correlate. In conclusion, the need for mechanistic studies in mouse models is highlighted to address the interplay between these components thought to be critical to asthma pathogenesis.
doi:10.4172/2155-6121.S1-008
PMCID: PMC3613782  PMID: 23560246
15.  Association of corticotropin releasing hormone receptor 2 (CRHR2) genetic variants with acute bronchodilator response in asthma 
Pharmacogenetics and genomics  2008;18(5):373-382.
Objective
Corticotropin - releasing hormone receptor 2 (CRHR2) participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short – acting β2 agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma.
Methods
We investigated 28 single nucleotide polymorphisms in CRHR2 for associations with acute bronchodilator response to albuterol in 607 Caucasian asthmatic subjects recruited as part of the Childhood Asthma Management Program (CAMP). Replication was conducted in two Caucasian adult asthma cohorts – a cohort of 427 subjects enrolled in a completed clinical trial conducted by Sepracor Inc. (MA, USA) and a cohort of 152 subjects enrolled in the Clinical Trial of Low-Dose Theopylline and Montelukast (LODO) conducted by the American Lung Association Asthma Clinical Research Centers.
Results
Five variants were significantly associated with acute bronchodilator response in at least one cohort (p-value ≤ 0.05). Variant rs7793837 was associated in CAMP and LODO (p-value = 0.05 and 0.03, respectively) and haplotype blocks residing at the 5’ end of CRHR2 were associated with response in all three cohorts.
Conclusion
We report for the first time, at the gene level, replicated associations between CRHR2 and acute bronchodilator response. While no single variant was significantly associated in all three cohorts, the findings that variants at the 5’ end of CRHR2 are associated in each of three cohorts strongly suggest that the causative variants reside in this region and its genetic effect, although present, is likely to be weak.
doi:10.1097/FPC.0b013e3282fa760a
PMCID: PMC3208318  PMID: 18408560
Asthma; genetics; corticotrophin releasing hormone receptor 2; CRHR2; bronchodilator response; polymorphism; β2 adrenergic receptor agonist
16.  Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene 
PLoS ONE  2013;8(2):e56179.
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
doi:10.1371/journal.pone.0056179
PMCID: PMC3572953  PMID: 23457522
17.  Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control and inflammation 
Background
Asthma in obese individuals is poorly understood, these patients are often refractory to standard therapy.
Objectives
To gain insights into the pathogenesis and treatment of asthma in obese individuals by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness and markers of asthmatic inflammation.
Methods
A prospective study of (i) asthmatic and non-asthmatic bariatric surgery patients compared at baseline, and (ii) asthmatic patients followed for 12 months after bariatric surgery.
Results
We studied 23 asthmatic and 21 non-asthmatic patients undergoing bariatric surgery. At baseline, asthmatics had lower FEV1 and FVC, and lower levels of lymphocytes in bronchoalveolar lavage.
Following surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score 1.55 to 0.74, p < 0.0001) and asthma quality of life (4.87 to 5.87, p < 0.0001). Airways responsiveness to methacholine improved significantly (PC20 3.9 to 7.28, p = 0.03). There was a statistically significant interaction between IgE status and change in airways responsiveness (p for interaction term = 0.01), improvement in AHR was significantly related to change in BMI in those with normal IgE (p = 0.02, R2 = 0.46). The proportion of lymphocytes in bronchoalveolar lavage and production of cytokines from activated peripheral blood CD4+ T cells increased significantly.
Conclusions
Bariatric surgery improves airway hyperresponsiveness in obese asthmatics with normal serum IgE. Weight loss has dichotomous effects on airway physiology and T cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.
doi:10.1016/j.jaci.2011.06.009
PMCID: PMC3164923  PMID: 21782230
Obesity; asthma; bariatric surgery; weight loss; airway hyperreactivity; CD4 T cell
18.  Asthma in the Elderly: Current Understanding and Future Research Needs 
Asthma in the elderly (AIE) is under diagnosed and under treated and there is a paucity of knowledge. The National Institute on Aging convened this workshop to identify what is known, what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of AIE. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger individuals but co-morbid illnesses and the psychosocial effects of aging may affect the diagnosis, clinical presentation and care of asthma in this population. At least two phenotypes exist among elderly asthma; those with long-standing asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiological mechanisms of AIE are likely to be different from those seen in young asthmatics and these differences may influence the clinical course and outcomes of asthma in this population.
doi:10.1016/j.jaci.2011.06.048
PMCID: PMC3164961  PMID: 21872730
Aging; airway; allergy; asthma; elderly; immune mechanisms; immunosenescence
19.  Effects of Obstructive Sleep Apnea and Gastroesophageal Reflux Disease on Asthma Control in Obesity 
Background
Obesity is a risk factor for asthma. Obese asthmatics often have poor asthma control and respond poorly to therapy. It has been suggested that co-morbidities associated with obesity, such as reflux and obstructive sleep apnea, could be important factors contributing to poor asthma control in obese patients.
Objectives
The purpose of this study was to determine if (i) reflux and/or (ii) symptoms of sleep apnea contribute to poor asthma control in obesity.
Methods
We studied asthmatic subjects participating in a trial of reflux treatment. Participants underwent baseline evaluation of asthma symptoms and lung function. 304 participants underwent esophageal pH probe testing. 246 participants were evaluated for obstructive sleep apnea symptoms.
Results
Of 402 participants in this trial, 51% were obese.
Role of reflux in asthma control
Those with higher body mass index reported a higher prevalence of reflux symptoms, but the prevalence of pH probe acid reflux was similar in all groups. Reflux was not associated with measures of asthma control in obese patients.
Role of obstructive sleep apnea in asthma control
Symptoms and self-report of obstructive sleep apnea were more common with increasing body mass index and associated with worse asthma control as measured by the Juniper Asthma Control Questionnaire and Asthma Symptom Utility Index.
Conclusions
Our data suggest that obstructive sleep apnea, but not gastroesophageal reflux disease may contribute significantly to poor asthma control in obese patients.
doi:10.3109/02770903.2011.601778
PMCID: PMC3171804  PMID: 21819338
Obesity; Asthma; lung function; reflux; obstructive sleep apnea
20.  Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene 
PLoS Genetics  2012;8(7):e1002824.
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS.
Author Summary
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function before and after the administration of short-acting β2-agonists, common medications used for asthma treatment. We performed a genome-wide association study of BDR with 1,644 white asthmatic subjects from six drug clinical trials and attempted to replicate these findings in 1,051 white subjects from two independent cohorts. The most significant associated variant was near the SPATS2L gene. We knocked down SPATS2L mRNA in human airway smooth muscle cells and found that β2-adrenergic receptor levels increased, suggesting that SPATS2L may be a regulator of BDR. Our results highlight the promise of pursuing GWAS results that do not necessarily reach genome-wide significance and are an example of how results from pharmacogenetic GWAS can be studied functionally.
doi:10.1371/journal.pgen.1002824
PMCID: PMC3390407  PMID: 22792082
21.  Regulatory Haplotypes in ARG1 Are Associated with Altered Bronchodilator Response 
Rationale: β2-agonists, the most common treatment for asthma, have a wide interindividual variability in response, which is partially attributed to genetic factors. We previously identified single nucleotide polymorphisms in the arginase 1 (ARG1) gene, which are associated with β2-agonist bronchodilator response (BDR).
Objectives: To identify cis-acting haplotypes in the ARG1 locus that are associated with BDR in patients with asthma and regulate gene expression in vitro.
Methods: We resequenced ARG1 in 96 individuals and identified three common, 5′ haplotypes (denoted 1, 2, and 3). A haplotype-based association analysis of BDR was performed in three independent, adult asthma drug trial populations. Next, each haplotype was cloned into vectors containing a luciferase reporter gene and transfected into human airway epithelial cells (BEAS-2B) to ascertain its effect on gene expression.
Measurements and Main Results: BDR varied by haplotype in each of the three populations with asthma. Individuals with haplotype 1 were more likely to have higher BDR, compared to those with haplotypes 2 and 3, which is supported by odds ratios of 1.25 (95% confidence interval, 1.03–1.71) and 2.18 (95% confidence interval, 1.34–2.52), respectively. Luciferase expression was 50% greater in cells transfected with haplotype 1 compared to haplotypes 2 and 3.
Conclusions: The identified ARG1 haplotypes seem to alter BDR and differentially regulate gene expression with a concordance of decreased BDR and reporter activity from haplotypes 2 and 3. These findings may facilitate pharmacogenetic tests to predict individuals who may benefit from other therapeutic agents in addition to β2-agonists for optimal asthma management.
Clinical trial registered with www.clinicaltrials.gov (NCT00156819, NCT00046644, and NCT00073840).
doi:10.1164/rccm.201005-0758OC
PMCID: PMC3056223  PMID: 20851928
pharmacogenetics; asthma; β2-agonist
22.  The Madison Avenue Effect: How drug presentation style influences adherence and outcome in patients with asthma 
Background
Little is known about how drug presentation influences medication adherence.
Objective
Examine the effect of an educational program aimed at increasing expectations of treatment benefit on medication adherence.
Methods
Data are analyzed from 99 participants who underwent electronic drug monitoring during TAPE (Trial of Asthma Patient Education), a randomized placebo-controlled multi-center trial. Participants with suboptimally-controlled asthma were randomized to placebo or montelukast in conjunction with a presentation mode that was either neutral or designed to increase outcome expectancy. Adherence was monitored electronically over 4 weeks, and was defined as ≥ 80% use of prescribed doses. Outcome expectancy, peak expiratory flow, pre-bronchodilator forced expiratory volume, asthma control (ACQ), and asthma-related quality of life were assessed at baseline and at the 4-week follow-up.
Results
Average electronic medication adherence was 69.9%. There was a significant interaction between presentation mode and drug assignment, with participants in the enhanced/montelukast group having a higher change in outcome expectancy (Δ 2.1 points, p < 0.001) and better medication adherence (odds ratio 4.0, CI 1.1, 14.3) compared to those in the neutral/placebo group. There was no difference in asthma symptoms, quality of life, or clinical outcomes based on presentation mode. Rather, increased outcome expectancy was associated with modest improvements in asthma symptoms after adjusting for presentation mode, drug assignment, and medication adherence.
Conclusion
The use of an enhanced presentation aimed at increasing outcome expectancy may lead to improved medication adherence.
doi:10.1016/j.jaci.2010.11.038
PMCID: PMC3050545  PMID: 21281871
Asthma; medication adherence; electronic monitoring; outcome expectancy; behavioral intervention
23.  Role of IL-6 in Asthma and Other Inflammatory Pulmonary Diseases 
The incidence and severity of chronic lung diseases is growing and affects between 100 and 150 million people worldwide and is associated with a significant rate of mortality. Unfortunately, the initial cause that triggers most chronic lung diseases remains unknown and current available therapies only ameliorate, but do not cure the disease. Thus, there is a need for identification of new targets and development of novel therapies especially for those most severely affected. IL-6, like other inflammatory cytokines, has been shown to be elevated in different lung diseases, but it was considered a byproduct of ongoing inflammation in the lung. However, recent studies support a dissociation of IL-6 from inflammation in the lung and suggest that this cytokine plays an active role in pathogenesis of asthma and, in all likelihood, COPD. IL-6 may therefore be a germane target for treatment of these and other chronic lung disease. Here, we provide an overview of the studies in mouse models and human patients that provide support for the involvement of IL-6 in lung diseases.
doi:10.7150/ijbs.4874
PMCID: PMC3491451  PMID: 23136556
IL-6; chronic lung diseases
24.  Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma 
Respiratory Research  2011;12(1):27.
Background
Inhaled short acting β2-agonists (SABA), e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR) and airway hyperresponsiveness (AHR) in mouse models of asthma.
Methods
Balb/C mice were sensitized and challenged with ovalbumin (OVA) and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS)-albuterol or the single isomers (S)- and (R)-albuterol twice daily over 7 days prior to harvest.
Results
We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse) was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol.
Conclusions
We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S)-albuterol, which lacks affinity for the β2-receptor, did not differ from (R)-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.
doi:10.1186/1465-9921-12-27
PMCID: PMC3060863  PMID: 21385381
25.  Randomized Trial of the Effect of Drug Presentation on Asthma Outcomes The American Lung Association Asthma Clinical Research Centers 
Background
Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma often improves with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit.
Objective
The study objective was to determine if response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit.
Methods
A randomized 20-center controlled trial enrolled 601 asthmatics with poor symptom control were assigned to one of five study groups. Participants were randomly assigned to either four treatment groups in a factorial design: placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages; or to usual care. Assignment to study drug was double-masked; assignment to message content was single-masked; usual care was not masked. The enhanced message aimed to increase expectation of benefit from the drug. The primary outcome was mean change in daily peak-flow over 4 weeks. Secondary outcomes included lung function and asthma symptom control.
Results
Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus neutral messages groups for either montelukast or placebo; no differences were noted between neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message, but not montelukast-treated participants; neutral placebo did have improved asthma control compared to usual care after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect.
Conclusions
Optimistic drug presentation augments the placebo effect for patient-reported outcomes (asthma control), but not lung function. However, the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness.
doi:10.1016/j.jaci.2009.05.041
PMCID: PMC2948850  PMID: 19632710

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