The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act (BPCA). The overall goal of the BPCA Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug labeling changes.
While significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled in children. In general, the younger the child, the less information there is available to guide clinicians. Since asthma often begins in early childhood, it is incumbent upon us to continue to address the primary questions raised in this review and carefully evaluate medications used to manage asthma in children.
Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.
Asthma; asthma natural history; asthma progression; asthma biomarkers; childhood asthma; asthma pharmacotherapy
Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD. The available ICSs vary in their therapeutic index and potency. Although ICSs are used in all age groups, younger and smaller children may be at a greater risk for adverse systemic effects because they can receive higher mg/kg doses of ICSs compared with older children. Most of the benefit from ICSs occurs in the low to medium dose range. Minimal additional improvement is seen with higher doses, although some patients may benefit from higher doses. Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial. When used appropriately, ICSs have few adverse events at low to medium doses, but risk increases with high-dose ICSs. Although several new drugs are being developed and evaluated, it is unlikely that any of these new medications will replace ICSs as the preferred initial long-term controller therapy for asthma, but more effective initial controller therapy could be developed for COPD.
asthma; asthma control; asthma guidelines; β-adrenergic agonists; corticosteroids
Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.
Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers.
Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks.
Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy.
A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.
Asthma exacerbations; Biomarkers; Dosing regimens; Inhaled corticosteroids; Omalizumab; Pharmacodynamics; Response predictors
Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described.
To describe individual and differential response of patients with asthma to salmeterol and tiotropium, when added to an ICS, as well as predictors of a positive clinical response.
Data from the double-blind, three-way crossover NHLBI Asthma Clinical Research Network’s TALC trial (ClinicalTrials.gov number, NCT00565266) were analyzed for individual and differential treatment responses to salmeterol and tiotropium, and predictors of a positive response to the endpoints FEV1, morning peak expiratory flow (AM PEF), and asthma control days (ACDs).
While approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of AM PEF (90 and 78, respectively), and ACDs (49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (104) than salmeterol (62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (OR 4.08 [CI 2.00–8.31], P < 0.001) and AM PEF (OR 2.12 [CI 1.12–4.01], P = 0.021), as did a decreased FEV1/FVC ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in the FEV1/FVC ratio). Higher cholinergic tone was also a predictor, while ethnicity, gender, atopy, IgE Level, sputum eosinophils, FENO, asthma duration, and BMI were not.
While these results need confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors which could help identify appropriate patients for this therapy.
asthma; tiotropium; salmeterol; responder analysis; predictor of response
The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.
Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.
Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses.
Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV1 (P < 10−4) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10−11). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10−7) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. TH2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function.
Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. TH1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.
Lung function; FEV1; asthma; TH1; IL12A; IL12RB1; STAT4; IRF2
Genome-wide association studies (GWAS) have emerged as a powerful tool to identify loci that affect drug response or susceptibility to adverse drug reactions. However, current GWAS based on a simple analysis of associations between genotype and phenotype ignores the biochemical reactions of drug response, thus limiting the scope of inference about its genetic architecture. To facilitate the inference of GWAS in pharmacogenomics, we sought to undertake the mathematical integration of the pharmacodynamic process of drug reactions through computational models. By estimating and testing the genetic control of pharmacodynamic and pharmacokinetic parameters, this mechanistic approach does not only enhance the biological and clinical relevance of significant genetic associations, but also improve the statistical power and robustness of gene detection. This report discusses the general principle and development of pharmacodynamics-based GWAS, highlights the practical use of this approach in addressing various pharmacogenomic problems, and suggests that this approach will be an important method to study the genetic architecture of drug responses or reactions.
asthma; asthma control; asthma guidelines; asthma impairment; asthma risk; asthma severity; biomarkers; genetics; inhaled corticosteroids
Over the past 20 years there has been a concerted effort in the United States to reduce morbidity related to chronic disease including asthma. Attention was initially directed towards asthma in response to the recognition that asthma mortality was increasing and that the burden of disease was significant. These efforts to address asthma mortality led to many new initiatives to develop clinical practice guidelines, implement the asthma guidelines into clinical practice, conduct research to fill the gaps in the guidelines, and to continuously revise the asthma guidelines as more information became available. An assessment of our progress shows significant accomplishments in relation to reducing asthma mortality and hospitalizations.
Consequently, we are now at a crossroads in asthma care. Although we have recognized some remarkable accomplishments in reducing asthma mortality and morbidity, the availability of new tools to monitor disease activity, including biomarkers and epigenetic markers, along with information technology systems to monitor asthma control hold some promise in identifying gaps in disease management. These advances should prompt the evolution of new strategies and new treatments to further reduce disease burden. It now becomes imperative to continue a focus on ways to further reduce the burden of asthma and prevent its onset.
Asthma; childhood asthma; asthma therapy; asthma statistics; asthma management; asthma guidelines; asthma disease management; inhaled corticosteroids; long-acting β-adrenergic agonists; leukotriene receptor antagonists; omalizumab; asthma surveillance; asthma mortality; asthma hospitalizations; asthma exacerbations; asthma progression; personalized medicine; public health
To identify the predictive factors of early childhood wheezing in children of low socioeconomic status.
The Childhood Asthma Prevention Study (CAPS) enrolled 177 low-income children (9–24 months old) with frequent wheezing. At age 7 years, presence of asthma was assessed through caregiver reports of physician diagnosis of asthma (CRPDA) and corroborated by assessment of bronchial hyperresponsiveness (BHR). Lung function, inflammatory markers, and asthma symptom severity were compared for children with ±CRPDA, ±BHR, and asthma. Baseline predictors for CRPDA, BHR and asthma at 7 years of age were examined.
Maternal symptom report strongly differentiated children with +CRPDA (50%) despite comparable airflow measurements (p<0.0001), and spirometric lung function measurements were different for +BHR (65%) vs. −BHR (p<0.005). Univariate analyses revealed different baseline predictors of +CRPDA and +BHR for children at age 7 years. Higher levels of maternal psychological resources were associated with +CRPDA, but not +BHR. Only 39% of children with a history of frequent wheezing met the conservative definition of asthma at age 7 years, with the following significant predictors found: low birth weight, baseline symptom severity and maternal psychological resources.
This low-income, multi-ethnic group of wheezing infants represents a unique population of children with distinct characteristics and risks for persistent asthma. Determination of asthma status at 7 years of age required objective measurement of BHR in addition to CRPDA. The association of maternal psychological resources with +CRPDA may represent a previously unrecognized factor in determination of asthma status among low-income groups.
Last year’s Advances in Pediatric Asthma concluded with the following statement “If we can close these [remaining] gaps through better communication, improvements in the health care system and new insights into treatment, we will move closer to better methods to intervene early in the course of the disease and induce clinical remission as quickly as possible in most children”. This year’s summary will focus on recent advances in pediatric asthma that take steps moving forward as reported in Journal of Allergy and Clinical Immunology publications in 2010.
Some of those recent reports show us how to improve asthma management through steps to better understand the natural history of asthma, individualize asthma care, reduce asthma exacerbations, manage inner city asthma, and some potential new ways to use available medications to improve asthma control. It is clear that we have made many significant gains in managing asthma in children but we have a ways to go to prevent asthma exacerbations, alter the natural history of the disease, and to reduce health disparities in asthma care.
Perhaps new directions in personalized medicine and improved health care access and communication will help maintain steady progress in alleviating the burden of this disease in children, especially young children.
asthma; asthma control; asthma impairment; asthma risk; asthma severity; early intervention in asthma; biomarkers; genetics; inhaled corticosteroids; leukotriene receptor antagonists; long-acting β-adrenergic agonists; omalizumab; personalized medicine; therapeutics
A subset of children with asthma respond better to leukotriene receptor antagonists (LTRA) than to inhaled corticosteroids (ICS). Information is needed to identify children with these preferential responses.
To determine whether the ratio of urinary leukotriene E4 to fractional exhaled nitric oxide (LTE4: FENO) delineates children with preferential responsiveness to montelukast (MT) compared to fluticasone propionate (FP) therapy.
Data from 318 children with mild to moderate asthma enrolled in 2 NHLBI CARE network studies (CLIC and PACT) were analyzed. The association between LTE4: FENO ratios at baseline and improved lung function or asthma control days (ACDs) with MT and FP therapy was determined and phenotypic characteristics related to high ratios was assessed.
LTE4: FENO ratios were associated with a greater response to MT than FP therapy for forced expiratory volume in 1 second (FEV1) measurements (2.1% increase per doubling of ratio, p=0.001) and for ACDs per week (0.3 increase, p= 0.009) in the CLIC study. In PACT, the ratio was associated with greater FEV1 responsiveness to MT than FP therapy (0.6% increase, p= 0.03). In a combined study analysis, LTE4: FENO ratios were associated with greater response to MT than FP therapy for FEV1 (0.8% increase, p=0.0005) and ACDs (0.3 increase, p=0.008). Children with LTE4: FENO ratios at or above the 75th percentile were likely (p<0.05) to be younger, female and exhibit lower levels of atopic markers and methacholine reactivity.
LTE4: FENO ratios predict a better response to MT than FP therapy in children with mild to moderate asthma.
In children with mild to moderate asthma, the LTE4: FENO ratio is associated with a better response to montelukast compared to fluticasone therapy.
Data from 318 children with mild to moderate asthma enrolled in 2 NHLBI network studies (CLIC and PACT) were analyzed. Urinary LTE4: FENO ratios predicted a better response to MT than FP therapy.
asthma; biomarkers; fluticasone propionate; inhaled corticosteroids; leukotriene E4; montelukast
Rationale: The function of the P2X7 nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied.
Objectives: To evaluate the association between P2X7, asthma exacerbations, and incomplete symptom control in a more diverse population.
Methods: A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X7 pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently.
Measurements and Main Results: A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β2-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2–6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1–9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV1 reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase.
Conclusions: P2X7 pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.
asthma; P2X7; exacerbation; Asthma Clinical Research Network; corticosteroids
In the past, we viewed lack of response to asthma medications as a rare event. Based on recent studies, we now expect significant variation in treatment response for all asthma medications. However, little information is available about methods to predict favorable treatment response. Research conducted in the National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) and the NHLBI Childhood Asthma Research and Education (CARE) Network verified this variability in response to several long-term control medications, specifically inhaled corticosteroids (ICS) and leukotriene receptor antagonists (LTRA), in adults and children with mild to moderate persistent asthma. The networks also identified potential methods to utilize patient characteristics, such as age and allergic status, and biomarkers, such as bronchodilator response, exhaled nitric oxide and urinary leukotrienes, to help predict response to ICS and LTRA and to determine which of the two treatments may be more effective in individual patients. This information now assists the clinician in personalizing asthma treatment at the time of initiating long-term control therapy.
Asthma; treatment response; inhaled corticosteroids; leukotriene receptor antagonists; leukotriene modifiers; β-adrenergic agonists
No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.
To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma.
Design, Setting, and Participants
A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n=114 assigned to physician assessment–based adjustment [101 completed], n=115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n=113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.
For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.
Main Outcome Measure
The primary outcome was time to treatment failure.
There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).
Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure.
clinicaltrials.gov Identifier: NCT00495157
Preliminary evidence is equivocal regarding the role of exhaled nitric oxide in clinical asthma management. This study evaluates the usefulness of eNO as an adjunct to asthma guidelines-based clinical care among inner-city adolescents and young adults.
A randomized, double-blind, parallel-group trial was conducted with 546 inner-city participants, aged 12–20 years, with persistent asthma (Clinicaltrials.gov Identifier: NCT00114413). A run-in characterization period of 3 weeks on an initial controller regimen preceded a 46-week double-blind treatment strategy. Participants were randomized to either, treatment based on NAEPP guidelines alone (Reference Group) or the guidelines plus FENO measurements (FENO Group). Primary outcome was asthma symptom days and secondary outcome was acute asthma exacerbations.
During the 46-week treatment period, the number of asthma symptom days, pulmonary function, unscheduled care visits, and hospitalizations did not differ between the treatment groups (mean asthma symptom days were 1.93 [95% CI 1.74-2.11] in the FENO group vs. 1.89 [1.71-1.74] in the control group; difference 0.04 [-0.29-0.22], p=0.7796). The FENO Group received a significantly higher inhaled corticosteroid dose (118.9 mcg/day difference, 95% CI: 48.5-189.3, P=0.0010) as compared to the Reference Group. Asthma symptoms remained low in both groups following randomization with 57% (306/534) of the participants well controlled for at least 80% of visits..
A coordinated asthma management program facilitated achieving good control in the majority of participants. The addition of FENO as a control indicator resulted in a higher dose of inhaled corticosteroids without a clinically important improvement in symptomatic asthma control.
asthma; biomarker; exhaled nitric oxide; inhaled corticosteroid; inner-city asthma; long-acting ß2-agonist; medication adherence; asthma exacerbations; asthma outcomes; asthma guidelines; impairment; risk
Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.
A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects.
The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1.
Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
Asthma; Airway hyperresponsiveness; Genome-wide association study; ITGB5; AGFG1
Patients with severe or difficult-to-treat asthma are an understudied population but account for considerable asthma morbidity, mortality, and costs. The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study was a large, 3-year, multicenter, observational cohort study of 4756 patients (n = 3489 adults ≥18 years of age, n = 497 adolescents 13-17 years of age, and n = 770 children 6-12 years of age) with severe or difficult-to-treat asthma. TENOR's primary objective was to characterize the natural history of disease in this cohort. Data assessed semiannually and annually included demographics, medical history, comorbidities, asthma control, asthma-related health care use, medication use, lung function, IgE levels, self-reported asthma triggers, and asthma-related quality of life. We highlight the key findings and clinical implications from more than 25 peer-reviewed TENOR publications. Regardless of age, patients with severe or difficult-to-treat asthma demonstrated high rates of health care use and substantial asthma burden despite receiving multiple long-term controller medications. Recent exacerbation history was the strongest predictor of future asthma exacerbations. Uncontrolled asthma, as defined by the 2007 National Heart, Lung, and Blood Institute guidelines’ impairment domain, was highly prevalent and predictive of future asthma exacerbations; this assessment can be used to identify high-risk patients. IgE and allergen sensitization played a role in the majority of severe or difficult-to-treat asthmatic patients.
TENOR; severe or difficult-to-treat asthma; asthma control; asthma exacerbations; burden; medication; quality of life; allergy; IgE
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4+ lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10−16). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV1). Though unadjusted linear models of FEV1 identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV1 and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.
ancestry; gene expression; population stratification; self-identified race
Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci.
Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma.
Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV1 in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma.
Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 × 10−6. Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10−5 for rs3127412 and 6.13 × 10−6 for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV1 response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP.
Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.
polymorphism; genome; pharmacogenomics; glucocorticoid
There is an association between adiposity and asthma prevalence, but the relationship to asthma control is unclear.
To understand the relationships among adiposity, gender, and asthma control in inner-city adolescents with asthma.
We prospectively followed 368 adolescents with moderate to severe asthma (ages 12–20 years) living in 10 urban areas for one year. Asthma symptoms and exacerbations were recorded, and pulmonary function and exhaled nitric oxide were measured every 6 weeks. Adiposity measures (BMI, DEXA scans) were made, and blood was collected for allergy markers, adiponectin, leptin, TNF-α, IL-6 and CRP.
More than 60% of females and 50% of males were above the 85th percentile of BMI-for-age. Higher BMI was associated with more symptom days (R= 0.18, P<0.01) and exacerbations (R=0.18, P=0.06) among females only. Adiponectin was inversely related to asthma symptoms (R=− 0.18, P<0.05) and exacerbations (R=− 0.20, P<0.05) and positively with FEV1/FVC (R=0.15, P<0.05) in males only, independent of body size. There was no relationship between adiposity or adipokines and total IgE, blood eosinophils and exhaled nitric oxide. DEXA provided little additional value in relating adiposity to asthma outcome in this population of adolescents.
Adiposity is associated with poorer asthma control in females. Adiponectin is associated with improved asthma control in males.
Obesity; Asthma; Adipokines; Leptin; Adiponectin
Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the EPR-3, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included.
Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma.
Twenty-six established asthma investigators, who are part of the NIH-supported Inner City Asthma Consortium (ICAC), participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma using the Asthma Control Evaluation (ACE) trial. CASI was validated using the Inner City Anti-IgE Therapy for Asthma (ICATA) trial.
CASI scores include five domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At ACE enrollment, CASI ranged from 0 to 17 with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than symptoms alone.
CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity, and provide a composite clinical characterization of asthma.
Asthma; composite score; morbidity; treatment; exacerbations; symptoms; severity
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.
Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited.
We sought to compare subjective and objective measurements of children’s adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes.
In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 μg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes.
Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, −0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes.
Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.
Asthma; adherence; compliance; children; lung growth; inhaled corticosteroids; budesonide; clinical trial
The effect on linear growth of daily long-term inhaled corticosteroid (ICS) therapy in preschool-aged children with recurrent wheezing is controversial.
To determine the effect of daily ICS given for 2 years on linear growth in preschool children with recurrent wheezing.
Children ages 2 and 3 years with recurrent wheezing and positive modified asthma predictive indices were randomized to a two-year treatment period of fluticasone propionate CFC (176 mcg/day) or masked-placebo delivered by valved chamber with mask and then followed 2 years off study medication. Height growth determined by stadiometry was compared between treatment groups.
In the study cohort as a whole, the fluticasone group did not have significantly less linear growth than the placebo-group [change in height from baseline difference (ΔHt) of −0.2 cm (95% CI, −1.1, 0.6)] two years after discontinuation of study treatment. In post-hoc analyses, children 2 years old and who weighed < 15 kg at enrollment treated with fluticasone had less linear growth compared to placebo [ΔHt of −1.6 cm (95% CI, −2.8, −0.4), p=0.009].
Linear growth was not significantly different in high-risk, recurrent wheezing preschool age children treated with CFC fluticasone 176 mcg/day compared to placebo 2 years after fluticasone is discontinued. However, post-hoc subgroup analyses revealed that children who are younger in age and of lesser weight relative to the entire study cohort had significantly less linear growth, possibly due to a higher relative fluticasone exposure.
Asthma predictive index; atopy; clinical trials; early childhood asthma; fluticasone; inhaled corticosteroids; intermittent wheezing; linear growth; research network