Asthma Clinical Research Articles

Canadian Thoracic Society 2012 guideline update: Diagnosis and management of asthma in preschoolers, children and adults: executive summary.

BACKGROUND: In 2010, the Canadian Thoracic Society (CTS) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older, and adults, including an updated Asthma Management Continuum. The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline update process, focusing, in this first iteration, on topics of controversy and/or gaps in the previous guidelines.METHODS: Four clinical questions were identified as a focus for the updated guideline: the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy; the initiation of adjunct therapy to inhaled corticosteroids (ICS) for uncontrolled asthma; the role of a single inhaler of an ICS/long-acting beta2-agonist combination as a reliever, and as a reliever and a controller; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan. The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics. In addition, literature searches were performed to identify relevant systematic reviews and randomized controlled trials. The panel formally assessed and graded the evidence, and made 34 recommendations.RESULTS: The updated guideline recommendations outline a role for inclusion of assessment of sputum eosinophils, in addition to standard measures of asthma control, to guide adjustment of controller therapy in adults with moderate to severe asthma. Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations. New recommendations for the adjustment of controller medication within written action plans are provided. Finally, priority areas for future research were identified.CONCLUSIONS: The present document is an executive summary of the first update of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee’s new guideline development process. Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide updates reflecting new evidence.

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 …

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.

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.

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.

Effect of Obesity on Asthma Phenotype is Dependent upon Asthma Severity

Background. We recently reported that obese and non-obese patients with asthma have similar airflow limitation and bronchodilator responsiveness, but obese patients have more symptoms overall. There is limited information on the effect of obesity on asthmatics of varying severity measured by objective physiological parameters. Understanding how obesity affects asthmatics of differing severity can provide insights into the pathogenesis of asthma in the obese and a rationale for the therapeutic approach to such patients. Methods. Participants with asthma from two American Lung Association—Asthma Clinical Research Center (ALA-ACRC) studies were grouped by tertiles of airflow obstruction (forced expiratory volume in one second (FEV1%) predicted, FEV1/forced vital capacity (FVC)) and methacholine reactivity (PC20FEV1). Within each tertile, we examined the independent effect of body mass index (BMI), divided into normal weight, overweight, and obese categories, on lung function, airway reactivity, and symptoms. Results. Overall, both FEV1 and FVC decreased and symptoms worsened with increasing BMI; airway reactivity was unchanged. When stratified by the degree of airflow obstruction, higher BMI was not associated with greater airway reactivity to methacholine. Higher BMI was associated with more asthma symptoms only in the least obstructed FEV1/FVC tertile. When stratified by degree of airway reactivity, BMI was inversely associated with FVC in all PC20FEV1 tertiles. BMI was directly associated with asthma symptoms only in those with the least airway reactivity. Conclusions. Obesity does not influence airway reactivity in patients with asthma and it is associated with more symptoms only in those with less severe disease.

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 . . .

Randomized trial of the effect of drug presentation on asthma outcomes: The American Lung Association Asthma Clinical Research Centers

Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit. The study objective was to determine whether response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit. A randomized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups. Participants were randomly assigned to one of 4 treatment groups in a factorial design (ie, 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, and 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. Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo; no differences were noted between the neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect. 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.

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

Improving adherence to asthma clinical guidelines and discharge documentation from emergency departments: Implementation of a dynamic and integrated electronic decision support system†

The authors previously developed a dynamic and integrated electronic decision support system called ACAFE (Asthma Clinical Assessment Form and Electronic decision support). The objective of this present study was to evaluate the effectiveness of this system on asthma management and documentation in an ED. Observational study using a pre- and post-intervention design, comparing patients managed using ACAFE after its implementation with historical controls. A systematic data abstraction process was used to compare patient records. A total of 50 patients were enrolled in the study group. These were compared with 50 historical controls. Use of ACAFE was associated with significantly higher rates of documentation of asthma severity (98% vs 18%, P < 0.01), as well as other clinically important variables, such as asthma precipitants, intensive care admission history and smoking history. ACAFE was also associated with significantly higher rate of asthma discharge plan documentation (76% vs 16%, P < 0.01), and this remained significant after adjustment for triage category and seniority of treating doctor in a regression model. The use of this decision support system in patients presenting to emergency with asthma was associated with improvements in clinical documentation and discharge management plans. Electronic decision support systems developed collaboratively with clinicians should play an important part of system-wide efforts to improve guideline adherence and compliance in ED.

Association of corticotropin-releasing hormone receptor-2 genetic variants with acute bronchodilator response in asthma.

Corticotropin-releasing hormone receptor (CRHR)-2 participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short-acting beta2-agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma. We investigated 28 single nucleotide polymorphisms in CRHR2 for associations with acute bronchodilator response to albuterol in 607 Caucasian asthmatic patients recruited as part of the Childhood Asthma Management Program. Replication was conducted in two Caucasian adult asthma cohorts--a cohort of 427 participants enrolled in a completed clinical trial conducted by Sepracor Inc. (Massachusetts, USA) and a cohort of 152 participants enrolled in the Clinical Trial of Low-Dose Theophylline and Montelukast conducted by the American Lung Association Asthma Clinical Research Centers. Five variants were significantly associated with acute bronchodilator response in at least one cohort (P<or=0.05). Variant rs7793837 was associated in Childhood Asthma Management Program and Low-Dose Theophylline and Montelukast (P=0.05 and 0.03, respectively) and haplotype blocks residing at the 5' end of CRHR2 were associated with response in all three cohorts. We report for the first time, at the gene level, replicated associations between CRHR2 and acute bronchodilator response. Although 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.

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

Once daily oral controller therapy with low dose theophylline or montelukast was not effective in poorly controlled asthma

Source Citation The American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit C...

Montelukast and Theophylline: No Use or Some Use in Persistent Asthma?

The recent study by the American Lung Association Asthma Clinical Research Centers suggests that prescribing montelukast or theophylline for symptomatic patients with asthma, irrespective of existing treatment, confers little further benefit (1). However, before extrapolating their findings into everyday clinical practice it is important to consider several points regarding the validity of the study. First, between 21 and 26% of randomized patients were not using regular inhaled corticosteroids, while the vast majority of these alarmingly appeared to be maintained on long-acting 2-agonists as monotherapy. Second, since the mean prebronchodilator FEV1 in the symptomatic patients with asthma enrolled was between 78 and 80% predicted, it would appear reasonable to consider that inhaled corticosteroids—a fundamental component in all but the mildest of asthma—should have been instituted in “real life” before consideration of montelukast or theophylline. Third, at the end of the 24-week study, as many as 40% of individuals failed to adhere to randomized treatment. Fourth, the spectrum of asthma severity appears to have varied considerably in the study, presumably with patients with an FEV1 of 50% of predicted up to normal values. Moreover, while some patients were receiving no treatment prior to study entry, up to 40%were receiving combined inhaled corticosteroid and long-acting 2-agonist preparations. Finally, the authors failed to evaluate effects on underlying airway inflammation or airway hyperresponsiveness, which are undoubtedly integral pathophysiological components of the underlying syndrome of asthma. In view of shortcomings such as inappropriate maintenance therapy during the study, patient heterogeneity, and failure to evaluate inflammatory biomarkers, it may be understandable that the authors failed to demonstrate any benefit with the addition of montelukast or theophylline. Moreover, these factors may also explain why the current findings appear to contradict those of others, in terms of beneficial effects of add-on montelukast in the correct clinical setting across a spectrum of asthma phenotypes (2).

Montelukast and Theophylline: No Use or Some Use in Persistent Asthma?

The recent study by the American Lung Association Asthma Clinical Research Centers suggests that prescribing montelukast or theophylline for symptomatic patients with asthma, irrespective of existing treatment, confers little further benefit (1). However, before extrapolating their findings into everyday clinical practice it is important to consider several points regarding the validity of the study. First, between 21 and 26% of randomized patients were not using regular inhaled corticosteroids, while the vast majority of these alarmingly appeared to be maintained on long-acting 2-agonists as monotherapy. Second, since the mean prebronchodilator FEV1 in the symptomatic patients with asthma enrolled was between 78 and 80% predicted, it would appear reasonable to consider that inhaled corticosteroids—a fundamental component in all but the mildest of asthma—should have been instituted in “real life” before consideration of montelukast or theophylline. Third, at the end of the 24-week study, as many as 40% of individuals failed to adhere to randomized treatment. Fourth, the spectrum of asthma severity appears to have varied considerably in the study, presumably with patients with an FEV1 of 50% of predicted up to normal values. Moreover, while some patients were receiving no treatment prior to study entry, up to 40%were receiving combined inhaled corticosteroid and long-acting 2-agonist preparations. Finally, the authors failed to evaluate effects on underlying airway inflammation or airway hyperresponsiveness, which are undoubtedly integral pathophysiological components of the underlying syndrome of asthma. In view of shortcomings such as inappropriate maintenance therapy during the study, patient heterogeneity, and failure to evaluate inflammatory biomarkers, it may be understandable that the authors failed to demonstrate any benefit with the addition of montelukast or theophylline. Moreover, these factors may also explain why the current findings appear to contradict those of others, in terms of beneficial effects of add-on montelukast in the correct clinical setting across a spectrum of asthma phenotypes (2).

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