Showing papers by "William W. Busse published in 2007"

Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program

Abstract: Background Severe asthma causes the majority of asthma morbidity. Understanding mechanisms that contribute to the development of severe disease is important. Objective The goal of the Severe Asthma Research Program is to identify and characterize subjects with severe asthma to understand pathophysiologic mechanisms in severe asthma. Methods We performed a comprehensive phenotypic characterization (questionnaires, atopy and pulmonary function testing, phlebotomy, exhaled nitric oxide) in subjects with severe and not severe asthma. Results A total of 438 subjects with asthma were studied (204 severe, 70 moderate, 164 mild). Severe subjects with asthma were older with longer disease duration ( P P ≤ .0001). Lung function was lower in severe asthma with marked bronchodilator reversibility ( P P = .0007), but blood eosinophils, IgE, and exhaled nitric oxide levels did not differentiate disease severity. A reduced FEV 1 , history of pneumonia, and fewer positive skin tests were risk factors for severe disease. Early disease onset (age P P = .002). Later disease onset (age ≥ 12 years) was associated with lower lung function and sinopulmonary infections ( P ≤ .02). Conclusion Severe asthma is characterized by abnormal lung function that is responsive to bronchodilators, a history of sinopulmonary infections, persistent symptoms, and increased health care utilization. Clinical implications Lung function abnormalities in severe asthma are reversible in most patients, and pneumonia is a risk factor for the development of severe disease.

A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma.

Abstract: Rationale: Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. In animal models, airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5. A previous small dose-finding study found that mepolizumab, a humanized anti–interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans.Objectives: To investigate the effect of three intravenous infusions of mepolizumab, 250 or 750 mg at monthly intervals, on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy (400–1,000 μg of beclomethasone or equivalent).Methods: Multicenter, randomized, double-blind, placebo-controlled study.Measurements and Main Results: Morning peak expiratory flow, forced expiratory volume in 1 second, daily β2-agonist use, symptom scores, exacerbation rates, and quality o...

Severe asthma in adults: what are the important questions?

Abstract: The term severe refractory asthma (SRA) in adults applies to patients who remain difficult to control despite extensive re-evaluation of diagnosis and management following an observational period of at least 6 months by a specialist. Factors that influence asthma control should be recognized and adequately addressed prior to confirming the diagnosis of SRA. This report presents statements according to the literature defining SRA in order address the important questions. Phenotyping SRA will improve our understanding of mechanisms, natural history, and prognosis. Female gender, obesity, and smoking are associated with SRA. Atopy is less frequent in SRA, but occupational sensitizers are common inducers of new-onset SRA. Viruses contribute to severe exacerbations and can persist in the airways for long periods. Inflammatory cells are in the airways of the majority of patients with SRA and persist despite steroid therapy. The T(H)2 immune process alone is inadequate to explain SRA. Reduced responsiveness to corticosteroids is common, and epithelial cell and smooth muscle abnormalities are found, contributing to airway narrowing. Large and small airway wall thickening is observed, but parenchymal abnormalities may influence airway limitation. Inhaled corticosteroids and bronchodilators are the mainstay of treatment, but patients with SRA remain uncontrolled, indicating a need for new therapies.

Severe asthma: Lessons from the Severe Asthma Research Program

Abstract: Severe asthma affects only a small percentage of the asthma population. However, these patients remain poorly understood and difficult to treat. Because the numbers are relatively small (10% or less of the asthma population), a network approach with shared protocols, samples, and data provides a unique opportunity to recruit the numbers of subjects necessary to perform adequately powered studies. The Severe Asthma Network (Severe Asthma Research Program) was established by the National Heart, Lung, and Blood Institute in 2001 to advance collectively the study of severe asthma to determine factors that differentiated these patients or subjects from those with milder asthma. Nearly 800 subjects have been recruited in less than 4 years to begin to address these differences. Future studies will specifically evaluate the role of inflammatory/oxidative processes, infection, genetics, and the distal lung in the pathogenesis of severe asthma.

IL4Rα Mutations Are Associated with Asthma Exacerbations and Mast Cell/IgE Expression

Abstract: Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor α (IL4Rα) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown.Hypothesis: Allelic substitutions in IL4Rα are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE.Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Rα. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE.Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more ...

Generation of Th1 and Th2 Chemokines by Human Eosinophils: Evidence for a Critical Role of TNF-α

Abstract: Emerging evidence suggests a role for eosinophils in immune regulation of T cells. Thus, we sought to determine whether human eosinophils may exert their effect via differential generation of Th1 and Th2 chemokines depending on cytokines in their microenvironment and, if so, to establish the conditions under which these chemokines are produced. Eosinophils cultured with TNF-alpha plus IL-4 had increased mRNA expression and protein secretion of the Th2-type chemokines, CCL17 (thymus and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine). Conversely, the Th1-type chemokines, CXCL9 (monokine induced by IFN-gamma) and CXCL10 (IFN-gamma-inducible protein-10), were expressed after stimulation with TNF-alpha plus IFN-gamma. Addition of TNF-alpha appeared to be essential for IFN-gamma-induced release of Th1-type chemokines and significantly enhanced IL-4-induced Th2-type chemokines. Inhibition of NF-kappaB completely blocked the production of both Th1 and Th2 chemokines. Activation of NF-kappaB, STAT6, and STAT1 was induced in eosinophils by TNF-alpha, IL-4, and IFN-gamma, respectively. However, there was no evidence for enhancement of these signaling events when eosinophils were stimulated with the combination of TNF-alpha plus IL-4 or TNF-alpha plus IFN-gamma. Thus, independently activated signaling cascades appear to lead to activation of NF-kappaB, STAT1, and STAT6, which may then cooperate at the promoter level to increase gene transcription. Our data demonstrate that TNF-alpha is a vital component for eosinophil chemokine generation and that, depending on the cytokines present in their microenvironment, eosinophils can promote either a Th2 or a Th1 immune response, supporting an immunoregulatory role for eosinophils.

Determinants of response to fluticasone propionate and salmeterol/fluticasone propionate combination in the Gaining Optimal Asthma controL study.

Abstract: Background During the Gaining Optimal Asthma controL study, 3416 patients with uncontrolled asthma were randomized to receive salmeterol/fluticasone propionate combination (SFC) or fluticasone propionate (FP) for 1 year. Approximately two thirds of patients achieved well-controlled (WC) asthma, and one third continued to have asthma that was not well controlled (NWC). Objective This analysis aimed to (1) identify factors influencing treatment response and (2) assess the clinical benefits of SFC and FP in patients with NWC asthma. Methods Logistic regression analysis was used to investigate whether covariates influenced the achievement of at least WC asthma in the study population. In patients with NWC asthma, predefined criteria were used to assess improvements in 6 clinical outcomes. Results Factors affecting the probability of having NWC asthma included smoking status (current vs never: odds ratio [OR], 2.757; 95% CI, 2.061−3.689; P P = 0.0273), sex (women vs men: OR, 0.652; 95% CI, 0.527–0.806; P P P Conclusion It is imperative for good asthma control that patients stop smoking. Patients who did not have at least WC asthma demonstrated clinical improvements in individual asthma outcomes. Clinical implications Although not all patients can achieve guideline-defined control, long-term treatment with SFC or FP is associated with clinical improvements in nearly all patients, regardless of smoking history or inhaled corticosteroid use.

Addressing issues of asthma in inner-city children.

Abstract: For children living in the inner city, asthma tends to be more frequent and severe. Although the causes for this heightened severity of asthma are not clearly established, environmental allergens likely play a major role. To characterize, understand, and treat children with asthma living in the inner city better, the National Institutes of Allergy and Infectious Diseases of the National Institutes of Health established an Inner City Asthma Program in 1991. Over the past 15 years, 3 separate inner-city asthma research networks have been formed and funded by this institute. The work from these programs has led to important observations including evidence that environmental allergens, particularly cockroach, are important for sensitization and severity of asthma of the affected children. Furthermore, reductions in the allergen load can lead to improved asthma control. The most recent program, the Inner City Asthma Consortium, was formed in 2002 with a goal to develop immune-based therapy for children with asthma in the inner city and to determine mechanisms of these therapies as well as immunopathogenesis of asthma in these high-risk children. This article reviews these programs and how they have begun the effort to understand and treat children with asthma who live in inner cities better and what their findings mean in relationship to unique features of asthma in inner city children.

Effect of omalizumab on the need for rescue systemic corticosteroid treatment in patients with moderate-to-severe persistent IgE-mediated allergic asthma: a pooled analysis.

Abstract: Background: Allergic asthma is an immunoglobulin E (IgE)-mediated disease characterized by frequent exacerbations following exposure to relevant allergens that leads to the development of chronic airway inflammation. Omalizumab, an anti-IgE antibody, reduces asthma exacerbation and hospitalization rates in patients with IgE-mediated allergic asthma. We investigated the effect of omalizumab on asthma outcomes in a retrospective pooled analysis of data from phase III clinical trials in patients (≥ 12 years) with moderate-to-severe persistent IgE-mediated allergic asthma.Methods: Systemic corticosteroid bursts and physician and patient overall assessments of asthma control were assessed in patients who received add-on omalizumab or current asthma therapy (control). The association of physician and patient overall assessments with the number of steroid bursts were also evaluated.Results: The analysis encompassed 4308 patients with moderate-to-severe persistent IgE-mediated allergic asthma (93% met GIN...

Rate of response of individual asthma control measures varies and may overestimate asthma control : An analysis of the GOAL study

Abstract: Background: Using a composite measure based on clinical outcomes, the GOAL study showed that achievement of Total Control of asthma was time dependent with the proportion of controlled patients continuing to rise through the year-long study. Taking data from this study, we compared time taken to achieve Total Control with time taken to achieve total control of each individual clinical criterion on treatment with salmeterol/fluticasone propionate (SFC) or fluticasone propionate (FP) alone. Methods: Time to achieving total control of individual outcomes (day-time symptoms, night-time awakenings, rescue medication use, PEF ≥80% predicted every day) were analyzed by Kaplan Meier plots and compared with achievement of composite Total Control. Results: Night-time awakenings responded most rapidly and daytime symptoms took longest to respond. After 12 weeks, the proportion of patients who achieved control of any individual clinical criterion was higher than the proportion who achieved control when using the comp...

The Safety and Efficacy of Zileuton Controlled-Release Tablets as Adjunctive Therapy to Usual Care in the Treatment of Moderate Persistent Asthma: A 6-Month Randomized Controlled Study

Abstract: This study was conducted to assess the safety and efficacy of zileuton controlled release [CR] 1,200 mg BID added to usual care (UC) in 926 patients with moderate asthma (619 patients randomized to zileuton CR and 307 to placebo). Sustained improvements in AM and PM peak expiratory flow (PEF) were observed in the zileuton CR group compared to placebo. The adverse event profile was similar in the two treatment groups. Eleven patients (1.8%) receiving zileuton CR and 2 (0.7%) receiving placebo experienced elevations of alanine aminotransferase (ALT) ≥ 3X the upper limit of normal (ULN). These elevations typically occurred (81.8%) during the first 3 months of exposure and most resolved within 21 days after discontinuation.

Human Rhinovirus Models in Asthma

Abstract: In both children and adults, rhinovirus (RV) infections remain a major cause of exacerbations in asthma. With the use of both in vitro models of RV infection and experimental models of asthma exacer

Cost-effectiveness of asthma control: an economic appraisal of the

Abstract: Background: The Gaining Optimal Asthma ControL (GOAL) study has shown the superiority of a combination of salmeterol/fluticasone propionate (SFC) compared with fluticasone propionate alone (FP) in terms of improving guideline defined asthma control. Methods: Clinical and economic data were taken from the GOAL study, supplemented with data on health related quality of life, in order to estimate the cost per quality adjusted life year (QALY) results for each of three strata (previously corticosteroid-free, low- and moderate-dose corticosteroid users). A series of statistical models of trial outcomes was used to construct cost effectiveness estimates across the strata of the multinational GOAL study including adjustment to the UK experience. Uncertainty was handled using the non-parametric bootstrap. Cost-effectiveness was compared with other treatments for chronic conditions. Result: Salmeterol/fluticasone propionate improved the proportion of patients achieving totally and well-controlled weeks resulting in a similar QALY gain across the three strata of GOAL. Additional costs of treatment were greatest in stratum 1 and least in stratum 3, with some of the costs offset by reduced health care resource use. Cost-effectiveness by stratum was £7600 (95% CI: £4800– 10 700) per QALY gained for stratum 3; £11 000 (£8600–14 600) per QALY gained for stratum 2; and £13 700 (£11 000–18 300) per QALY gained for stratum 1. Conclusion: The GOAL study previously demonstrated the improvement in total control associated with the use of SFC compared with FP alone. This study suggests that this improvement in control is associated with cost-perQALY figures that compare favourably with other uses of scarce health care resources.