Center for Pharmacogenomics and Translational Research

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Center for Pharmacogenomics and Translational Research

Federal Way, FL, United States
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Lang J.E.,Nemours Childrens Hospital | Hossain M.J.,DuPont Company | Lima J.J.,Center for Pharmacogenomics and Translational Research
Journal of Allergy and Clinical Immunology | Year: 2015

Background Past studies of asthma in overweight/obese children have been inconsistent. The reason overweight/obese children commonly report worse asthma control remains unclear. Objective To determine qualitative differences in symptoms between lean and overweight/obese children with early-onset, atopic asthma. Methods We conducted a cross-sectional analytic study of lean (20% to 65% body mass index) and overweight/obese (≤85% body mass index) 10-to 17-year-old children with persistent, early-onset asthma. Participants completed 2 to 3 visits to provide a complete history, qualitative and quantitative asthma symptom characterization, and lung function testing. We determined associations between weight status and symptoms using multivariable linear and logistic regression methods. Results Overweight/obese and lean asthmatic children displayed similar lung function. Despite lower fraction of exhaled nitric oxide (30.0 vs 62.6 ppb; P =.037) and reduced methacholine responsiveness (PC20FEV1 1.87 vs 0.45 mg/mL; P <.012), overweight/obese children reported more than thrice frequent rescue treatments (3.7 vs 1.1 treatments/wk; P =.0002) than did lean children. Weight status affected the child's primary symptom reported with loss of asthma control (Fisher exact test; P =.003); overweight/obese children more often reported shortness of breath (odds ratio = 11.8; 95% CI, 1.41-98.7) and less often reported cough (odds ratio = 0.26; 95% CI, 0.08-0.82). Gastroesophageal reflux scores were higher in overweight/obese children (9.6 vs 23.2; P =.003) and appear to mediate overweight/obesity-related asthma symptoms. Conclusions Overweight/obese children with early-onset asthma display poorer asthma control and a distinct pattern of symptoms. Greater shortness of breath and β-agonist use appears to be partially mediated via esophageal reflux symptoms. Overweight children with asthma may falsely attribute exertional dyspnea and esophageal reflux to asthma, leading to excess rescue medication use. © 2014 American Academy of Allergy, Asthma & Immunology.

Lang J.E.,Nemours Childrens Hospital | Blake K.V.,Center for Pharmacogenomics and Translational Research
Pharmacogenomics and Personalized Medicine | Year: 2013

Asthma is one of the most common chronic diseases affecting children. Despite publicized expert panels on asthma management and the availability of high-potency inhaled corticosteroids, asthma continues to pose an enormous burden on quality of life for children. Research into the genetic and molecular origins of asthma are starting to show how distinct disease entities exist within the syndrome of "asthma". Biomarkers can be used to diagnose underlying molecular mechanisms that can predict the natural course of disease or likely response to drug treatment. The progress of personalized medicine in the care of children with asthma is still in its infancy. We are not yet able to apply stratified asthma treatments based on molecular phenotypes, although that time may be fast approaching. This review discusses some of the recent advances in asthma genetics and the use of current biomarkers that can help guide improved treatment. For example, the fraction of expired nitric oxide and serum Immunoglobulin E (IgE) (including allergen-specific IgE), when evaluated in the context of recurrent asthma symptoms, are general predictors of allergic airway inflammation. Biomarker assays for secondhand tobacco smoke exposure and cysteinyl leukotrienes are both promising areas of study that can help personalize management, not just for pharmacologic management, but also education and prevention efforts. © 2013 Lang and Blake, publisher and licensee Dove Medical Press Ltd.

Blake K.,Center for Pharmacogenomics and Translational Research | Mehta R.,Glaxosmithkline | Spencer T.,Childrens Hospital | Kunka R.L.,Glaxosmithkline | Hendeles L.,University of Florida
European Respiratory Journal | Year: 2012

We determined lung bioavailability of a fluticasone propionate (FP) pressurised metred-dose inhaler (Flovent® HFA; GlaxoSmithKline, Research Triangle Park, NC, USA) administered via AeroChamber Plus® (Monaghan Medical, Plattsburgh, NY, USA) with Facemask and Babyhaler®(GlaxoSmithKline) valved holding chambers (VHCs) using a population pharmacokinetic approach. Children from 1 to <4 yrs of age with stable asthma but a clinical need for inhaled corticosteroid therapy were administered 88 mg FP hydrofluoroalkane (2 x 44 μg) twice daily delivered through the two devices in an open-label, randomised crossover manner for 8 days each. Patients were randomised to one of three sparse sampling schedules for blood collection throughout the 12-h dosing interval on the 8th day of each treatment for pharmacokinetic analysis. The area under the FP plasma concentration - time curve (AUC) was determined for each regimen. 17 children completed the study. The population mean AUC following FP with AeroChamber Plus® with Facemask was 97.45 pg·h·mL -1 (95% CI 85.49-113.32 pg·h·mL -1) and with Babyhaler®was 51.55 pg·h·mL -1 (95% CI 34.45-64.46 pg·h·mL -1). The relative bioavailability (Babyhaler®/AeroChamber Plus®) was 0.53 (95% CI 0.30-0.75). Clinically significant differences in lung bioavailability were observed between the devices. VHCs are not interchangeable, as differences in drug delivery to the lung may occur. A population pharmacokinetic approach can be used to determine lung bioavailability of FP. Copyright©ERS 2012.

Blake K.,Center for Pharmacogenomics and Translational Research | Teague W.G.,University of Virginia
Current Opinion in Pulmonary Medicine | Year: 2013

PURPOSE OF REVIEW: Gastroesophageal reflux disease (GERD) is common in children with asthma and may be present with or without symptoms. Clinicians, influenced by position statements in national guidelines, have routinely treated children with poorly controlled asthma with various anti-GERD medications. This practice is based on the pervasive but unproven belief that GERD is an important determinant of poor asthma control. RECENT FINDINGS: Clinical studies show that GERD is highly prevalent in children with asthma, with estimates as high as 80%, but nearly half of the children are asymptomatic. However, there is no conclusive evidence per se that asymptomatic GERD informs asthma control, and treatment of GERD in the few controlled trials available for review does not substantively improve asthma outcomes. In a recent large controlled clinical trial, treatment with a proton-pump inhibitor (PPI) was not only ineffective, but adverse effects were common, including an increased prevalence of symptomatic respiratory infections. SUMMARY: Current evidence does not support the routine use of anti-GERD medications in the treatment of poorly controlled asthma of childhood. However large controlled trials of children symptomatic of both GERD and asthma have not been conducted, and in this case the benefits of treatment, although unproven, might outweigh the risks. Copyright © 2012 Lippincott Williams &Wilkins.

Lima J.J.,Center for Pharmacogenomics and Translational Research | Franciosi J.P.,Gasteroenterology Nemours Childrens Hospital
Pharmacogenomics | Year: 2014

The use of proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux and related diseases is increasing, especially in the pediatric population. Prolonged use of PPIs has been associated with several adverse effects, including potentially life-threatening gastric and respiratory infections, which are related to dose or to the degree of gastric acid suppression. Genetic variation in the CYP2C19 gene gives rise to poor and extensive metabolizer phenotypes, which influence PPI clearance, efficacy and exposure. A recent paper linked lansoprazole-associated respiratory infections in children with the poor metabolizer phenotype. The case is made for implementing pharmacogenomic testing for the CYP2C19-PPI gene-drug pair and to dose accordingly in order to minimize PPI-associated infections. © 2014 Future Medicine Ltd.

Lang J.E.,Center for Pharmacogenomics and Translational Research | Hossain J.,DuPont Company | Hossain J.,University of Delaware | Dixon A.E.,University of Vermont | And 4 more authors.
Chest | Year: 2011

Background: The relationship between obesity and asthma remains inadequately defined. Studies about how obesity affects asthma control and lung function show conflicting results. Additional focus on the effect of age as a modifier may make clearer the interaction between obesity and asthma phenotype. We sought to use a diverse and well-phenotyped cohort of asthmatic patients to determine how age impacts the relationship between obesity and spirometry, peak flow variability, airflow perception, and asthma control. Methods: The characteristics of 490 patients with mild persistent asthma taken from 2,794 study visits from a prospective trial studying strategies of step-down therapy were included in this post hoc analysis. A longitudinal mixed-effect model was used to determine if age affects the relationship between obesity and asthma characteristics, including spirometry, asthma control, airway pH, and perception of airflow changes. Results: The effect of obesity on asthma outcomes changes with age and gender. Obese 6- to 11-year-old children had the largest reduction in lung function but reported relatively fewer asthma symptoms than did similar nonobese asthmatics. Obese 12- to 17-year-olds showed a trend toward greater airflow obstruction and asthma symptoms compared with nonobese asthmatics. Adults in general displayed few obesity-related alterations in asthma phenotype. Female gender among 12- to 17- and 18- to 44-year-olds was associated with greater obesity-related asthma impairment. Conclusions: Age is a significant effect modifier on the relationship between obesity and asthma phenotype. With increasing age, the influence of obesity on the asthma phenotype is generally reduced. The asthma phenotype may be most impacted by obesity among children and women. Trial registry:; No.: NCT00156819; URL: © 2011 American College of Chest Physicians.

Raissy H.H.,University of New Mexico | Blake K.,Center for Pharmacogenomics and Translational Research
Pediatric, Allergy, Immunology, and Pulmonology | Year: 2012

Diagnosis and management of asthma in preschool children are challenging. The Expert Panel Report 3 has recommendations for specific illness phenotypes to start long-term controller medication to reduce risk and impairment in children ages 0-4-year old. The use of daily-inhaled corticosteroids has shown to be effective in preschool children with persistent asthma, but there are also reports of growth retardation. For children with recurrent or intermittent wheezing without symptoms in between episodes, the intermittent use of controller medications may be an option for certain phenotypes. This review will discuss the available data on use of intermittent controller medications in preschool children with wheezing. © 2012 Mary Ann Liebert, Inc.

Lang J.E.,Center for Pharmacogenomics and Translational Research
Pediatric, Allergy, Immunology, and Pulmonology | Year: 2012

Obesity rates have increased dramatically among children in many parts of the world, especially in North America and several other English-speaking countries. The impact of obesity on pediatric health has become a major prevention initiative by the Obama administration and several public health organizations. Children with obesity are at increased risk for developing asthma, which is already one of the most common chronic diseases among children. The cause underlying obesity's impact on asthma risk is unknown. Commonly cited potential etiologies include airway smooth muscle dysfunction from thoracic restriction, obesity-related circulating inflammation priming the lung, and obesity-related comorbidities mediating asthma symptom development. Each of these theories does not fit precisely with all of the data that have accumulated over the last decade. In this review, I will explore other possible causes including: (1) dietary characteristics common in Westernized countries that might lead to both obesity and asthma; (2) reductions in physical activity; and (3) genetic alterations that increase the propensity to both obesity and asthma together. Next, I will review the current data on how obesity affects common characteristics of asthma such as airway inflammation, lung function, risk of exacerbation, atopy, and response to treatment. Obesity in children with asthma appears to be associated with greater airflow obstruction and a mildly diminished response to inhaled corticosteroids. Little objective evidence in children suggests that obesity significantly heightens the risk of exacerbation or worsens disease stability in children. Lastly, I will discuss the current literature that suggests that obese children with asthma generally should receive the same guidelines-based management as lean children. However, interventions that encourage daily physical activity, weight-loss, normalization of nutrient levels, and monitoring of common obesity-related sequelae should be considered by healthcare providers managing obese children with difficult-to-control asthma. © 2012 Mary Ann Liebert, Inc.

Blake K.,Center for Pharmacogenomics and Translational Research | Lima J.,Center for Pharmacogenomics and Translational Research
Expert Opinion on Drug Metabolism and Toxicology | Year: 2015

Introduction: Long-acting β2-agonists are an effective class of drugs, when combined with inhaled corticosteroids, for reducing symptoms and exacerbations in patients with asthma that is not adequately controlled by inhaled corticosteroids alone. However, because this class of drugs has been associated with severe adverse events, including hospitalization and death in small numbers of patients, efforts to identify a pharmacogenetic profile for patients at risk has been diligently investigated. Areas covered: The PubMed search engine of the National Library of Medicine was used to identify English-language and non-English language articles published from 1947 to March 2015 pertinent to asthma, pharmacogenomics, and long-acting β2-agonists. Keywords and topics included: asthma, asthma control, long-acting β2-agonists, salmeterol, formoterol, pharmacogenetics, and pharmacogenomics. This strategy was also used for the Cochrane Library Database and CINAHL. Reference types were randomized controlled trials, reviews, and editorials. Additional publications were culled from reference lists. The publications were reviewed by the authors and those most relevant were used to support the topics covered in this review. Expert opinion: Children, who carry the ADRB2 Arg16Arg genotype, may be at greater risk than adults for severe adverse events. Rare ADRB2 variants appear to provide better clues for identifying the at-risk population of asthmatics. © 2015 Taylor & Francis.

Lima J.J.,Center for Pharmacogenomics and Translational Research
Expert Opinion on Drug Metabolism and Toxicology | Year: 2014

Introduction: Short- and long-acting β agonists (SABA and LABA) are bronchodilators for treating asthma. Bronchodilator response (BDR) is quantified by measuring air expired in the first second during a forced expiratory maneuver, prior to and following inhalation of SABA. BDR has been associated with a significant degree of heterogeneity, in part attributable to genetic variation. Heritability, the proportion of phenotypic variability accounted for by genetic variation is estimated to account for 50% of pulmonary function and 28.5% for BDR. Areas covered: A MEDLINE search for English articles published from January 1990 to June 2014 was completed using the terms: bronchodilator, bronchodilator response, short-acting bronchodilator, long-acting bronchodilator, β2 adrenergic receptor gene (ADRB2), asthma and pharmacogenomics. The effects of ADRB2 variants on BDR and the safety of SABA and LABA + inhaled corticosteroids have been studied with equivocal results. Single and candidate gene studies have identified variants in other genes that alter response to bronchodilators. Associations were recently observed between hospital admission rates and two rare ADRB2 polymorphisms: Thr164Ile and a 25 base pair insertion-deletion at nucleotide -376. This was the first report of life-threatening events associated with LABA being linked to rare ADRB2 variants. Expert opinion: Pharmacogenomic studies over the last two decades clearly demonstrate that polymorphisms alter patient response to bronchodilators in patients with asthma. © 2014 Informa UK, Ltd.

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