Lung Association Asthma Clinical Research Research Articles

Effect of a Soy Isoflavone Supplement on Lung Function and Clinical Outcomes in Patients With Poorly Controlled Asthma: A Randomized Clinical Trial

A number of studies have suggested a potential role for dietary factors as modifiers of asthma severity. This study assessed whether a soy isoflavone supplement improves asthma control in patients with poorly controlled asthma.Three hundred eighty-six subjects ≥12 years old with symptomatic, poorly controlled asthma were enrolled from 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network.In this multicenter, randomized, double-blind, placebo-controlled trial, subjects were randomized (1:1) to receive either a soy isoflavone supplement or placebo twice daily for 6 months. The primary outcome measure was forced expiratory volume in 1 second (FEV1). Secondary outcomes included the Asthma Control Test score, the Asthma Symptoms Utility Index, and the Marx Asthma Quality of Life Questionnaire or Children’s Health Survey for Asthma for participants aged 12 to 16 years. Other outcomes included peak expiratory flow, symptom-free days, and rates of episodes of poor asthma control. Exhaled nitric oxide, peripheral blood eosinophil count, serum interleukin-6, serum C-reactive protein, urinary leukotriene E4, and quantification of total blood genistein level were also assessed.Mean changes in prebronchodilator FEV1 over 6 months were not significantly different between the placebo group (0.03 L, 95% confidence interval: –0.01 to 0.08 L) and the soy isoflavone group (0.01 L; 95% confidence interval: –0.07 to 0.07 L). No differences were observed for the other parameters measures when the placebo group was compared with the soy isoflavone group. Mean plasma genistein level increased from 4.87 to 37.67 ng/mL (P < .001) in participants receiving the supplement.In this study of adolescent and adult patients with poorly controlled asthma, use of a soy isoflavone supplement did not result in improved lung function or clinical outcomes compared with placebo.The authors had previously shown a relationship between dietary intake of the soy isoflavone genistein and improvement in FEV1 in a cross-sectional analysis of participants with varying asthma severity enrolled in a multicenter clinical trial. However, the results of this study do not support the use of soy isoflavone supplementation for patients with poorly controlled asthma. This highlights the limitations of cross-sectional, population-based studies of dietary nutrient intake and the use of surrogate markers of disease to predict clinically relevant outcomes in interventional studies for asthma.

Effect of a Soy Isoflavone Supplement on Lung Function and Clinical Outcomes in Patients With Poorly Controlled Asthma

Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% CI, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. clinicaltrials.gov Identifier: NCT01052116.

Editorial introductions

Editorial introductions

The American Lung Association: Asthma Clinical Research Centers network: addressing real life questions in asthma management

Clinical trials are designed to answer specific questions regarding the safety, efficacy and effectiveness of biomedical or behavioral interventions in human subjects. Results from clinical trials have led to many breakthroughs in disease prevention and treatment, and provided evidence to support optimal standards of care into clinical or public health practice. Clinical trials form the evidence base for clinical treatment guidelines. The American Lung Association Asthma Clinical Research Centers network is a multicenter clinical trials’ network based in the USA that has significantly contributed to the evidence base for asthma management in both adults and pediatric patients. The purpose of this paper is to provide an overview of how selected Asthma Clinical Research Center studies have affected the treatment and the management of asthma over the past 13 years.

Editorial introductions

Editorial introductions

Sex differences in asthma symptom profiles and control in the American Lung Association Asthma Clinical Research Centers

Important differences between men and women with asthma have been demonstrated, with women describing more symptoms and worse asthma-related quality of life (QOL) despite having similar or better pulmonary function. While current guidelines focus heavily on assessing asthma control, they lack information about whether sex-specific approaches to asthma assessment should be considered. We sought to determine if sex differences in asthma control or symptom profiles exist in the well-characterized population of participants in the American Lung Association Asthma Clinical Research Centers (ALA-ACRC) trials. We reviewed baseline data from four trials published by the ALA-ACRC to evaluate individual item responses to three standardized asthma questionnaires: the Juniper Asthma Control Questionnaire (ACQ), the multi-attribute Asthma Symptom Utility Index (ASUI), and Juniper Mini Asthma Quality of Life Questionnaire (mini-AQLQ). In the poorly-controlled population, women reported similar overall asthma control (mean ACQ 1.9 vs. 1.8; p=0.54), but were more likely to report specific symptoms such as nocturnal awakenings, activity limitations, and shortness of breath on individual item responses. Women reported worse asthma-related QOL on the mini-AQLQ (mean 4.5 vs. 4.9; p<0.001) and more asthma-related symptoms with a lower mean score on the ASUI (0.73 vs. 0.77; p≤0.0001) and were more likely to report feeling bothered by particular symptoms such as coughing, or environmental triggers. In participants with poorly-controlled asthma, women had outwardly similar asthma control, but had unique symptom profiles on detailed item analyses which were evident on evaluation of three standardized asthma questionnaires.

Editorial introductions

Editorial introductions

Asthma clinical trials of American Lung Association/Asthma Clinical Research Centers (ALA-ACRC): what have we learned in 12 years?

The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) is a research network focused on performing clinical trials that directly affect medical care for adults and children with asthma. The group of eighteen clinical research centers and a data-coordinating center perform studies supported by the American Lung Association, the National Institute of Health/National Heart Lung and Blood Institute (NIH/NHLBI), and partnership with industry. The network has completed and published eight clinical trials (seven randomized control trials and one validation study of a diagnostic tool), numerous ancillary studies, and has four ongoing trials at the time of publication of this review. The network’s trials have focused on areas such as the relative merits of different adjunctive treatments for asthma not controlled on inhaled corticosteroids (ICS) alone, the effect of treatment of comorbid diseases on asthma care, and studies evaluating techniques used in the conduct of clinical trials of treatments for asthma. This review will describe the accomplishments of our network to date and the effect of those accomplishments on asthma care.

Lansoprazole of no benefit in children with asthma

Writing Committee for the American Lung Association Asthma Clinical Research C, Holbrook JT, Wise RA, Gold BD, Blake K, Brown ED, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA 2012;307:373-81.

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.

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.

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.

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).

T-Cell Responses and Hypersensitivity to Influenza and Egg Antigens Among Adults with Asthma Immunized with the Influenza Vaccine

<h2>Abstract</h2><h3>Background</h3> The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) reported that the inactivated influenza vaccine is safe for patients with asthma and recommended its use to reduce the morbidity associated with infection. <h3>Objective</h3> Because the ALA-ACRC's recommendation would include vaccination of all patients with asthma, including those with severe asthma and first-time vaccinees, we conducted a parallel study to address whether patients with asthma who report bronchospasm after vaccination might be demonstrating a hypersensitivity response to the vaccine. <h3>Methods</h3> Thirty-two adult patients with asthma from the ALA-ACRC cohort were recruited. Subjects were randomly assigned to receive influenza vaccine or placebo and then recorded asthma symptoms and peak expiratory flow rates for 14 days. On day 14, influenza vaccine and egg antigen–induced mononuclear cell proliferation and IFN-γ, IL-5, and IL-4 production were measured and compared with symptoms. <h3>Results</h3> Increased influenza but not egg antigen–induced mononuclear cell proliferation was present among vaccinated subjects. These responses were unrelated to asthma exacerbations after vaccine. There were no differences in cytokine production in response to either influenza or egg antigen in association with asthma exacerbations. <h3>Conclusions</h3> Episodes of bronchospasm after influenza vaccination do not seem related to hypersensitivity to the vaccine.

T-cell responses and hypersensitivity to influenza and egg antigens among adults with asthma immunized with the influenza vaccine

Background The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) reported that the inactivated influenza vaccine is safe for patients with asthma and recommended its use to reduce the morbidity associated with infection. Objective Because the ALA-ACRC's recommendation would include vaccination of all patients with asthma, including those with severe asthma and first-time vaccinees, we conducted a parallel study to address whether patients with asthma who report bronchospasm after vaccination might be demonstrating a hypersensitivity response to the vaccine. Methods Thirty-two adult patients with asthma from the ALA-ACRC cohort were recruited. Subjects were randomly assigned to receive influenza vaccine or placebo and then recorded asthma symptoms and peak expiratory flow rates for 14 days. On day 14, influenza vaccine and egg antigen–induced mononuclear cell proliferation and IFN-γ, IL-5, and IL-4 production were measured and compared with symptoms. Results Increased influenza but not egg antigen–induced mononuclear cell proliferation was present among vaccinated subjects. These responses were unrelated to asthma exacerbations after vaccine. There were no differences in cytokine production in response to either influenza or egg antigen in association with asthma exacerbations. Conclusions Episodes of bronchospasm after influenza vaccination do not seem related to hypersensitivity to the vaccine.

Inactivated influenza vaccine is safe for children and adults with stable asthma

(2001) N Engl J Med 345, 1529. American Lung Association Asthma Clinical Research Centers. . The safety of inactivated influenza vaccine in adults and children with asthma. . Nov 22;...

The inactivated trivalent split-virus influenza vaccine was safe in stable asthma

Source Citation American Lung Association Asthma Clinical Research Centers. The safety of inactivated influenza vaccine in adults and children with asthma. N Engl J Med. 2001 Nov 22;345:1529-36. 11...