Asthma Clinical Research Network Research Articles

Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials

Minority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk. We evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations. One thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n=760). Twenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P=.30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P=.13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P=.74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P=.03]). Black subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect.

Obesity's effect on asthma extends to diagnostic criteria

The use of inflammatory biomarkers to delineate the type of lung inflammation present in asthmatic subjects is increasingly common. However, the effect of obesity on these markers is unknown. We aimed to determine the effect of obesity on conventional markers of inflammation in asthmatic subjects. We performed secondary analysis of data from 652 subjects previously enrolled in 2 Asthma Clinical Research Network trials. We performed linear correlations between biomarkers and logistic regression analysis to determine the predictive value of IgE levels, blood eosinophil counts, and fraction of exhaled nitric oxide values in relationship to sputum eosinophil counts (>2%), as well as to determine whether cut points existed that would maximize the sensitivity and specificity for predicting sputum eosinophilia in the 3 weight groups. Overall, statistically significant but relatively weak correlations were observed among all 4 markers of inflammation. Within obese subjects, the only significant correlation found was between IgE levels and blood eosinophil counts (r=0.33, P<.001); furthermore, all other correlations between inflammatory markers were approximately 0, including correlations with sputum eosinophil counts. In addition, the predictive value of each biomarker alone or in combination was poor in obese subjects. In fact, in obese subjects none of the biomarkers of inflammation significantly predicted the presence of high sputum eosinophil counts. Obese asthmatic subjects have lower cut points for IgE levels (268 IU), fraction of exhaled nitric oxide values (14.5ppb), and blood eosinophil counts (96cells/μL) than all other groups. In obese asthmatic subjects conventional biomarkers of inflammation are poorly predictive of eosinophilic airway inflammation. As such, biomarkers currently used to delineate eosinophilic inflammation in asthmatic subjects should be approached with caution in these subjects.

Race is associated with differences in airway inflammation in patients with asthma

African American subjects have a greater burden from asthma compared with white subjects. Whether the pattern of airway inflammation differs between African American and white subjects is unclear. We sought to compare sputum airway inflammatory phenotypes of African American and white subjects treated or not with inhaled corticosteroids (ICSs; ICS+ and ICS-, respectively). We performed a secondary analysis of self-identified African American and white subjects with asthma enrolled in clinical trials conducted by the National Heart, Lung, and Blood Institute-sponsored Asthma Clinical Research Network and AsthmaNet. Demographics, clinical characteristics, and sputum cytology after sputum induction were examined. We used a sputum eosinophil 2% cut point to define subjects with either an eosinophilic (≥2%) or noneosinophilic (<2%) inflammatory phenotype. Among 1018 participants, African American subjects (n=264) had a lower FEV1 percent predicted (80% vs 85%, P<.01), greater total IgE levels (197 vs 120 IU/mL,P<.01), and a greater proportion with uncontrolled asthma (43% vs 28%, P<.01) compared with white subjects (n=754). There were 922 subjects in the ICS+group (248 African American and 674 white subjects) and 298 subjects in the ICS- group (49 African American and 249 white subjects). Eosinophilic airway inflammation was not significantly different between African American and white subjects in either group (percentage with eosinophilic phenotype: ICS+group: 19% vs 16%, P=.28; ICS- group: 39% vs 35%, P=.65; respectively). However, when adjusted for confounding factors, African American subjects were more likely to exhibit eosinophilic airway inflammation than white subjects in the ICS+group (odds ratio, 1.58; 95% CI, 1.01-2.48; P=.046) but not in the ICS-group (P=.984). African American subjects exhibit greater eosinophilic airway inflammation, which might explain the greater asthma burden in this population.

Impact of Age and Sex on Response to Asthma Therapy.

Age and sex are associated with differences in asthma prevalence and morbidity. To determine if age and sex associate with distinct phenotypes and a variable response to therapy in subjects with mild to moderate asthma. We used Asthma Clinical Research Network data to determine the impact of age and sex on phenotypes and treatment failures among subjects participating in 10 trials from 1993 to 2003. A total of 1,200 subjects were identified (median age, 30.4 yr; male, 520 [43.3%]; female, 680 [56.7%]) and analyzed. A higher proportion of subjects greater than or equal to 30 years old experienced treatment failures (17.3% vs. 10.3%; odds ratio [OR], 1.82; confidence interval [CI], 1.30-2.54; P < 0.001), and rates increased proportionally with increasing age older than 30 across the cohort (OR per yr, 1.02 [CI, 1.01-1.04]; OR per 5 yr, 1.13 [CI, 1.04-1.22]; P < 0.001). Lower lung function and longer duration of asthma were associated with a higher risk of treatment failures. A higher proportion of subjects greater than or equal to 30 years old receiving controller therapy experienced treatment failures. When stratified by specific therapy, treatment failures increased consistently for every year older than age 30 in subjects on inhaled corticosteroids (OR per year, 1.03; CI, 1.01-1.07). Females had a slightly higher FEV1 % predicted (84.5% vs. 81.1%; P < 0.001) but similar asthma control measures. There was not a statistically significant difference in treatment failures between females and males (15.2% vs. 11.7%; P = 0.088). Older age is associated with an increased risk of treatment failure, particularly in subjects taking inhaled corticosteroids. There was no significant difference in treatment failures between sexes.

Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids

To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10(-8) (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10(-5)), rs2388639 (combined P = 8.56 × 10(-9)), and rs10044254 (combined P = 9.16 × 10(-8)) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.

Physician-, biomarker-, and symptom-based adjustment of inhaled corticosteroids for asthma had similar effects

Source Citation Calhoun WJ, Ameredes BT, King TS, et al; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. Comparison of physician-, biomarker-, and symptom-based s...

Inhaled Corticosteroid Dose Adjustment in Mild Persistent Asthma

REGULAR USE OF CONTROLLER MEDICATIONS, SUCH AS INhaledcorticosteroids(ICS), improvesoutcomesinpatientswithasthma.Theimportanceofdailyuseof ICS is emphasized in asthma management guidelines. However, ensuring that patients with asthma adhere to daily useof ICS,evenwhenasymptomatic, is achallenge.Therefore, cliniciansspendsubstantial timeandenergyeducatingpatients with asthma about the importance of daily use of ICS. The latter medications, however, do not lead to the immediate relief of asthmasymptomsassociatedwithshort-actingrescuebronchodilators, such as albuterol, so patients often neglect to take ICS due to the incorrect perception that they do not help. This frequently observed pattern of poor adherence to daily use of ICShasledtothehypothesisthattyinguseofICStotheas-needed use of a short-acting bronchodilator may lead to better asthma control forpatientswithrelativelymildasthma.Combininguse of ICS with as-needed short-acting bronchodilators may improve asthma control by increasing the patient’s motivation to take ICS and by focusing ICS therapy on periods when symptoms of asthma (which vary over time due to environmental factors) are more prounounced. This as-needed ICS strategy could also potentially reduce costs and patient inconvenience by avoiding use of ICS when asthma is not bothersome. In this issue of JAMA, Calhoun et al report the results of the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial comparing as-needed, symptom-based use of ICS, as well as a biomarker-based dosing strategy, with traditional everyday use of ICS with dosing determined by a physician. In this randomized controlled trial, conducted by the National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network (ACRN), the investigators randomly assigned adults with mild to moderate persistent asthma (defined as acceptable symptom control and lung function while receiving low-dose ICS therapy) to 1 of 3 strategies for dose adjustment of ICS: physician assessment–based adjustment (n=114 patients), in which the physician prescribes a regular twice-daily ICS dose, which is guided by the National Asthma Education and Prevention Program (NAEPP) guidelines, at clinic visits approximately every 6 weeks; symptombased adjustment (n=113 patients), in which patients are instructed to take 2 puffs of beclomethasone HFA (40 μg/puff) whenever taking 2 puffs of albuterol to relieve asthma symptoms; or biomarker-based adjustment (n=115 patients) in which ICS dosing is adjusted according to the concentration of exhaled nitric oxide, which was measured every 6 weeks. During the 36-week follow-up, the time to clinical worsening of asthma (the primary outcome measure of the trial) did not differ in the primary comparisons of symptombased adjustment vs physician assessment–based adjustment or of biomarker-based adjustment vs physician assessment–based adjustment. Nine-month rates of clinical failure estimated by Kaplan-Meier analysis were 22% for the physician assessment–based adjustment group, 15% for the symptom-based adjustment group, and 20% for the biomarker-based adjustment group. Participants in the symptom-based adjustment group took significantly less ICS per month than the other groups. This outcome was 1 of 18 secondary outcome measures, and most of these did not differ significantly among the treatment groups; thus, this finding should be interpreted with caution. This report adds to prior randomized trials that have compared the typical physician-prescribed dosing of ICS with intermittent dosing guided by symptoms for patients with relatively mild asthma. A prior ACRN study of adults with mild persistent asthma indicated that a strategy of initiating a course of inhaled or oral corticosteroid only when asthma symptoms became bothersome (according to a written action plan), led to a similar peak expiratory flow rate and asthma exacerbation rate as the everyday physician-prescribed dosing of controller medications (ICS or leukotriene antagonist), although some outcomes such as bronchial reactivity and symptom-free days were improved by regular twice-daily use of ICS. Like the BASALT trial, the prior ACRN study was designed to show superiority of one strategy over another, rather than to test equivalence, and the lack of superiority of any strategy over the others must be interpreted accordingly. Taking a different approach to intermittent ICS treatment, European investigators conducted an equivalence study comparing asneeded use of an inhaler containing both the short-acting bronchodilator albuterol and beclomethasone (a combination inhaler not available in the United States) with the traditional approach of regular twice daily beclomethasone and as-

Key observations from the NHLBI Asthma Clinical Research Network

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,...

Use of the Asthma Control Questionnaire by the Asthma Clinical Research Network

To the Editors: In our original report previously published in the European Respiratory Journal ( ERJ ) [1], the Asthma Clinical Research Network (ACRN) utilised an unauthorised modified version of the Asthma Control Questionnaire (ACQ)# administered over the telephone to demonstrate that the severity of a cold measured within the first 2 days was a predictor of subsequent worsening of asthma control. We subsequently …

Asthma Clinical Research Network: Lessons Learned

The Asthma Clinical Research Network was created by the National Heart, Lung, and Blood Institute to improve public health by rapidly evaluating novel and existing therapeutic approaches to asthma. The multicenter clinical research network has greatly contributed to the healthcare community's understanding of asthma by conducting clinical trials independent of the pharmaceutical industry. The following manuscript reviews the experimental design and major findings of noteworthy studies performed in this network. All of the network's publications were reviewed, and 19 were selected for summary. As shown in these publications, the research performed by the Asthma Clinical Research Network has produced significant data with important implications that should impact the way the healthcare community treats asthma at the present time.

Impact of race on asthma treatment failures in the asthma clinical research network.

Recent studies suggest that people with asthma of different racial backgrounds may respond differently to various therapies. To use data from well-characterized participants in prior Asthma Clinical Research Network (ACRN) trials to determine whether racial differences affected asthma treatment failures. We analyzed baseline phenotypes and treatment failure rates (worsening asthma resulting in systemic corticosteroid use, hospitalization, emergency department visit, prolonged decrease in peak expiratory flow, increase in albuterol use, or safety concerns) in subjects participating in 10 ACRN trials (1993-2003). Self-declared race was reported in each trial and treatment failure rates were stratified by race. A total of 1,200 unique subjects (whites = 795 [66%]; African Americans = 233 [19%]; others = 172 [14%]; mean age = 32) were included in the analyses. At baseline, African Americans had fewer asthma symptoms (P < 0.001) and less average daily rescue inhaler use (P = 0.007) than whites. There were no differences in baseline FEV(1) (% predicted); asthma quality of life; bronchial hyperreactivity; or exhaled nitric oxide concentrations. A total of 147 treatment failures were observed; a significantly higher proportion of African Americans (19.7%; n = 46) experienced a treatment failure compared with whites (12.7%; n = 101) (odds ratio = 1.7; 95% confidence interval, 1.2-2.5; P = 0.007). When stratified by treatment, African Americans receiving long-acting β-agonists were twice as likely as whites to experience a treatment failure (odds ratio = 2.1; 95% confidence interval, 1.3-3.6; P = 0.004), even when used with other controller therapies. Despite having fewer asthma symptoms and less rescue β-agonist use, African-Americans with asthma have more treatment failures compared with whites, especially when taking long-acting β-agonists.

Matrix-based Concordance Correlation Coefficient for Repeated Measures

In many clinical studies, Lin's concordance correlation coefficient (CCC) is a common tool to assess the agreement of a continuous response measured by two raters or methods. However, the need for measures of agreement may arise for more complex situations, such as when the responses are measured on more than one occasion by each rater or method. In this work, we propose a new CCC in the presence of repeated measurements, called the matrix-based concordance correlation coefficient (MCCC) based on a matrix norm that possesses the properties needed to characterize the level of agreement between two p× 1 vectors of random variables. It can be shown that the MCCC reduces to Lin's CCC when p= 1. For inference, we propose an estimator for the MCCC based on U-statistics. Furthermore, we derive the asymptotic distribution of the estimator of the MCCC, which is proven to be normal. The simulation studies confirm that overall in terms of accuracy, precision, and coverage probability, the estimator of the MCCC works very well in general cases especially when n is greater than 40. Finally, we use real data from an Asthma Clinical Research Network (ACRN) study and the Penn State Young Women's Health Study for demonstration.

2007 San Diego Wildfires and Asthmatics

Context. This case series reports the changes in the respiratory health of eight asthmatic subjects and the relationship with air quality associated with the October 2007 firestorm in San Diego County of California. Case presentation. Participants were eight subjects with asthma enrolled in Asthma Clinical Research Network (ACRN) (NIH# U10-HL074218) studies at the University of California San Diego (UCSD), School of Medicine, who had study data collected immediately prior, during and 1 month after the 5-day firestorm in San Diego County. Air quality deteriorated to an extreme average of 71.5 mg/m3 small particulate matter less than 2.5 μm (PM2.5) during the firestorm. Respiratory health data included morning and evening peak expiratory flow rates (PEFR), morning and evening Forced Expiratory Volume in one second (FEV1), rescue medication usage, and sputum eosinophils. Morning and evening PEFR and FEV1 rates remained stable. The two subjects tested during the fires had elevated eosinophil counts and rescue medication usage was increased in five of the eight subjects. Discussion. Pulmonary function test values were stable during the wildfires for all eight subjects but there was a statistically significant increase in rescue medication usage during the wildfires that correlated with PM2.5 values. The two subjects tested during the fires showed increases in sputum eosinophil counts consistent with increased airways inflammation. Relevance. These findings suggest that poor air quality associated with wildfires resulted in an increase in airways inflammation in these asthmatic subjects, but pulmonary function tests remained stable, possibly due to increased rescue medication usage. This is especially pertinent as there is an increase in incidence of wildfires this decade.

Products at Risk

In this issue of the Journal, we publish the results of a clinical trial investigating step-up control in adult patients with asthma whose disease was not well controlled by low-dose inhaled glucocorticoids.1 This study, which compared the utility of treating such patients with inhaled tiotropium bromide, inhaled salmeterol, or higher doses of inhaled glucocorticoids, was conceived and implemented by the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network (ACRN). The study constitutes comparative effectiveness research, in which the products of a number of different companies are compared in a well-defined clinical setting. Simply put, the companies' products are . . .

Body mass index and phenotype in subjects with mild-to-moderate persistent asthma

Although obesity has been hypothesized to worsen asthma, data from studies of subjects with well-characterized asthma are lacking. We sought to evaluate the relationship between body mass index (BMI), asthma impairment, and response to therapy. BMI (in kilograms per meter squared) and asthma phenotypic and treatment response data were extracted from Asthma Clinical Research Network studies. The cross-sectional relationship between BMI and asthma impairment was analyzed, as was the longitudinal relationship between BMI and response to asthma controller therapies. One thousand two hundred sixty-five subjects with mild-to-moderate persistent asthma were evaluated. Analyses of lean versus overweight/obese asthmatic subjects demonstrated small differences in FEV1 (3.05 vs 2.91 L, P = .001), FEV1/forced vital capacity ratio (mean, 83.5% vs 82.4%; P = .01), rescue albuterol use (1.1 vs 1.2 puffs per day, P = .03), and asthma-related quality of life (5.77 vs 5.59, P = .0004). Overweight/obese asthmatic subjects demonstrated a smaller improvement in exhaled nitric oxide levels with inhaled corticosteroid (ICS) treatment than did lean asthmatic subjects (3.6 vs 6.5 ppb, P = .04). With ICS/long-acting beta-agonist treatment, overweight/obese asthmatic subjects demonstrated smaller improvements in lung function than lean asthmatic subjects, with an 80 mL (P = .04) and 1.7% (P = .02) lesser improvement in FEV1 and FEV1/forced vital capacity ratio, respectively. Significant differences in therapeutic response to leukotriene modifiers between BMI categories were not observed. Increased BMI is not associated with clinically significant worsening of impairment in subjects with mild-to-moderate persistent asthma. There is a modest association between increased BMI and reduced therapeutic effect of ICS-containing regimens in this patient population. Prospective studies evaluating the effect of being overweight or obese on treatment response in asthma are warranted.

A Quick Round Up of News and Information from Our Community

A Quick Round Up of News and Information from Our Community

Aeroallergen sensitization correlates with PC 20 and exhaled nitric oxide in subjects with mild-to-moderate asthma

Aeroallergen sensitization in adult asthmatic patients from a wide geographic area has not been correlated with patients' characteristics, markers of airways inflammation, and lung function. We assessed data obtained from the Asthma Clinical Research Network trials to determine the relationship of aeroallergen sensitization to age, sex, ethnicity, and markers of inflammation and airways function. Skin testing (14 epicutaneous) was performed on 1338 subjects with objectively diagnosed mild-to-moderate asthma from 11 Asthma Clinical Research Network studies. Skin testing used identical techniques and a quality assurance program to ensure uniformity across centers. Ninety-five percent of the subjects had at least 1 positive skin test response. Of these, 14% had positive reactions to 1 or 2 allergens and 81% had positive reactions to 3 or more allergens, and 2% of subjects reacted only to seasonal allergens, 26% only to perennial allergens, and 67% to both. Increasing IgE and exhaled nitric oxide values, decreasing PC(20) values, and minority ethnicity significantly correlated with the number of positive skin test responses. Subjects with late-onset asthma were less likely to be sensitized; nonetheless, 89% of subjects older than 60 years had positive responses. Ninety-five percent of patients with mild-to-moderate asthma might have an allergic component. Age does not significantly affect aeroallergen sensitization, but the pattern of allergic sensitization varies with ethnicity and geography. Measures used to characterize asthma, such as IgE, exhaled nitric oxide, and PC(20) values, are correlated with aeroallergen sensitization.

Exploration of the β2-adrenergic receptor regulatory regions: the next step in the holy grail of asthma pharmacogenetics research

exploration of the β2-adrenergic receptor (ADRB2) has been the holy grail of asthma pharmacogenetics research since the gene was cloned two decades ago. The evolution in our understanding of genetic variants in the ADRB2 reflects both the progress and the limitations in exploring the contributions

A matched crossover design for clinical trials

Two design principles are used frequently in clinical trials: 1) A subject is “matched” or “paired” with a similar subject to reduce the chance that other variables obscure the primary comparison of interest. 2) A subject serves as his/her own control by “crossing over” from one treatment to another during the course of an experiment. There are situations in which it may be advantageous to use the two design principles — crossing over and matching — simultaneously. That is, it may be advantageous to conduct a “paired crossover design,” in which each subject, while paired with a similar subject, crosses over and receives each experimental treatment. In this paper, we describe two clinical trials conducted by the National Heart, Lung and Blood Institute's Asthma Clinical Research Network that used a paired 2 × 2 crossover design. The Beta Adrenergic Response by GEnotype (BARGE) Study compared the effects of regular use of inhaled albuterol on mildly asthmatic patients with different genotypes at the 16th position of the beta-agonist receptor gene. The Smoking Modulates Outcomes of Glucocorticoid (SMOG) Therapy in Asthma Study evaluated the hypothesis that smoking reduces the response to inhaled corticosteroids. For such paired crossover designs, the primary parameter of interest is typically the treatment-by-pairing interaction term. In evaluating the relative efficiency of the paired 2 × 2 crossover design to two independent crossover designs with respect to this interaction term, we show that the paired 2 × 2 crossover design is more efficient if the correlations between the paired members on the same treatments are greater than their correlations on different treatments. This condition should hold in most circumstances, and therefore the paired crossover design deserves serious consideration for any clinical trial in which the crossing over and matching of subjects is deemed simultaneously beneficial.

Guideline-defining asthma clinical trials of the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network

Guideline-defining asthma clinical trials of the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network