J. Mark FitzGerald

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

BACKGROUND Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. Georges Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Effects of an Anti-TSLP Antibody on Allergen-Induced Asthmatic Responses

BACKGROUND Thymic stromal lymphopoietin (TSLP) is an epithelial-cell-derived cytokine that may be important in initiating allergic inflammation. AMG 157 is a human anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents receptor interaction. METHODS In this double-blind, placebo-controlled study, we randomly assigned 31 patients with mild allergic asthma to receive three monthly doses of AMG 157 (700 mg) or placebo intravenously. We conducted allergen challenges on days 42 and 84 to evaluate the effect of AMG 157 in reducing the maximum percentage decrease in the forced expiratory volume in 1 second (FEV1). We also measured the fraction of nitric oxide in exhaled air, blood and sputum eosinophils, and airway hyperresponsiveness. The primary end point was the late asthmatic response, as measured 3 to 7 hours after the allergen challenge. RESULTS AMG 157 attenuated most measures of allergen-induced early and late asthmatic responses. The maximum percentage decrease in the FEV1 during the late response was 34.0% smaller in the AMG-157 group than in the placebo group on day 42 (P=0.09) and 45.9% smaller on day 84 (P=0.02). In addition, patients receiving AMG 157 had significant decreases in levels of blood and sputum eosinophils before and after the allergen challenge and in the fraction of exhaled nitric oxide. There were 15 adverse events in the AMG-157 group, as compared with 12 in the placebo group; there were no serious adverse events. CONCLUSIONS Treatment with AMG 157 reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge. These findings are consistent with a key role for TSLP in allergen-induced airway responses and persistent airway inflammation in patients with allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined from these data. (Funded by Amgen; ClinicalTrials.gov number, NCT01405963.).

A summary of the new GINA strategy: a roadmap to asthma control

Over the past 20 years, the Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many national guidelines. However, uptake of existing guidelines is poor. A major revision of the GINA report was published in 2014, and updated in 2015, reflecting an evolving understanding of heterogeneous airways disease, a broader evidence base, increasing interest in targeted treatment, and evidence about effective implementation approaches. During development of the report, the clinical utility of recommendations and strategies for their practical implementation were considered in parallel with the scientific evidence. This article provides a summary of key changes in the GINA report, and their rationale. The changes include a revised asthma definition; tools for assessing symptom control and risk factors for adverse outcomes; expanded indications for inhaled corticosteroid therapy; a framework for targeted treatment based on phenotype, modifiable risk factors, patient preference, and practical issues; optimisation of medication effectiveness by addressing inhaler technique and adherence; revised recommendations about written asthma action plans; diagnosis and initial treatment of the asthma−chronic obstructive pulmonary disease overlap syndrome; diagnosis in wheezing pre-school children; and updated strategies for adaptation and implementation of GINA recommendations. This paper summarises key changes in the GINA global strategy report, a practical new resource for asthma care http://ow.ly/ObvYi

Overdiagnosis of asthma in obese and nonobese adults

Background: It is unclear whether asthma is overdiagnosed in developed countries, particularly among obese individuals, who may be more likely than nonobese people to experience dyspnea. Methods: We conducted a longitudinal study involving nonobese (body mass index 20–25) and obese (body mass index ≥ 30) individuals with asthma that had been diagnosed by a physician. Participants were recruited from 8 Canadian cities by means of random-digit dialing. A diagnosis of current asthma was excluded in those who did not have evidence of acute worsening of asthma symptoms, reversible airflow obstruction or bronchial hyperresponsiveness, despite being weaned off asthma medications. We stopped asthma medications in those in whom a diagnosis of asthma was excluded and assessed their clinical outcomes over 6 months. Results: Of 540 individuals with physician-diagnosed asthma who participated in the study, 496 (242 obese and 254 nonobese) could be conclusively assessed for a diagnosis of asthma. Asthma was ultimately excluded in 31.8% (95% confidence interval [CI] 26.3%–37.9%) in the obese group and in 28.7% (95% CI 23.5%–34.6%) in the nonobese group. Overdiagnosis of asthma was no more likely to occur among obese individuals than among nonobese individuals (p = 0.46). Of those in whom asthma was excluded, 65.5% did not need to take asthma medication or seek health care services because of asthma symptoms during a 6-month follow-up period. Interpretation: About one-third of obese and nonobese individuals with physician-diagnosed asthma did not have asthma when objectively assessed. This finding suggests that, in developed countries such as Canada, asthma is overdiagnosed.

Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis

Background Numerous studies with varying associations between domestic use of solid biomass fuels (wood, dung, crop residue, charcoal) and respiratory diseases have been reported. Objective To present the current data systematically associating use of biomass fuels with respiratory outcomes in rural women and children. Methods Systematic searches were conducted in 13 electronic databases. Data were abstracted from original articles that satisfied selection criteria for meta-analyses. Publication bias and heterogeneity of samples were tested. Studies with common diagnoses were analysed using random-effect models. Results A total of 2717 studies were identified. Fifty-one studies were selected for data extraction and 25 studies were suitable for meta-analysis. The overall pooled ORs indicate significant associations with acute respiratory infection in children (OR 3.53, 95% CI 1.94 to 6.43), chronic bronchitis in women (OR 2.52, 95% CI 1.88 to 3.38) and chronic obstructive pulmonary disease in women (OR 2.40, 95% CI 1.47 to 3.93). In contrast, no significant association with asthma in children or women was noted. Conclusion Biomass fuel exposure is associated with diverse respiratory diseases in rural populations. Concerted efforts in improving stove design and lowering exposure to smoke emission may reduce respiratory disease associated with biomass fuel exposure.

Effects of Interleukin-13 Blockade on Allergen-induced Airway Responses in Mild Atopic Asthma

RATIONALE Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity. OBJECTIVES We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma. METHODS Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils. MEASUREMENTS AND MAIN RESULTS The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P < 0.05), but this effect was lost by Day 35. Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35. There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils. The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo. CONCLUSIONS IL-13 has a role in allergen-induced airway responses in humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.

Canadian Asthma Consensus Conference Summary of Recommendations

The Asthma Committee of the Canadian Thoracic Society invited a group of Canadian physicians with a particular interest in asthma to meet in Montebello, Quebec, March 9-12, 1995 to arrive at a consensus statement on the optimal approach to the management of asthma in the pediatric and adult ambulatory care settings. The societies and associations represented are listed in the appendix with the names of the contributors to this document. The objectives of the Montebello conference were: 1. To review the current ambulatory care management of asthma in Canada; 2. To develop guidelines with the participation of family physicians and specialists; 3. To develop guidelines which are evidence-based; 4. In creating evidence-based guidelines to focus attention on aspects of asthma management that are currently not supported by randomized controlled trials; 5. To develop strategies that allow for the implementation of rational guidelines at a local level. Recommendations were based on a critical review of the scientific literature by small groups prior to the meeting and are categorized according to the strength of the scientific evidence supporting each recommendation (Table 1).

Adult Asthma Consensus Guidelines Update 2003

BACKGROUND Several sets of Canadian guidelines for the diagnosis and management of asthma have been published over the past 15 years. Since the last revision of the 1999 Canadian Asthma Consensus Report, important new studies have highlighted the need to incorporate new information into the asthma guidelines. OBJECTIVES To review the literature on adult asthma management published between January 2000 and June 2003; to evaluate the influence of the new evidence on the recommendations made in the 1999 Canadian Asthma Consensus Guidelines and its 2001 update; and to report new recommendations on adult asthma management. METHODS Three specific topics for which new evidence affected the previous recommendations were selected for review: initial treatment of asthma, add-on therapies in the treatment of asthma and asthma education. The resultant reviews were discussed in June 2003 at a meeting under the auspices of the Canadian Thoracic Society, and recommendations for adult asthma management were reviewed. RESULTS The present report emphasises the importance of the early introduction of inhaled corticosteroids in symptomatic patients with mild asthma; stresses the benefit of adding additional therapy, preferably long-acting beta2-agonists, to patients incompletely controlled on low doses of inhaled corticosteroids; and documents the essential role of asthma education. CONCLUSION The present report generally supports many of the previous recommendations published in the 1999 Canadian Asthma Consensus Report and provides higher levels of evidence for a number of those recommendations.

Asthma control in Canada remains suboptimal: The Reality of Asthma Control (TRAC) study

BACKGROUND Two Canadian studies showed that 55% of patients with asthma had daily symptoms (in 1996) and that 57% of patients suffered from poorly controlled asthma (in 1999). OBJECTIVES To assess the state of asthma control of adult Canadians, and asthma knowledge and practices of Canadian physicians actively involved in the care of patients with asthma. METHODS Telephone interviews were conducted with adults 18 to 54 years of age who had been diagnosed with asthma at least six months before the survey, who did not have chronic obstructive pulmonary disease and who had a smoking history of fewer than 20 pack-years. Physicians were surveyed by telephone and mail. The surveys took place between April and August 2004. RESULTS Almost all (97%) of the 893 patients believed that they had controlled asthma; however, only 47% had controlled disease according to symptom-based guideline criteria. Just 39% of 463 physicians based their treatment recommendations on the Canadian asthma guidelines most or all of the time, despite having a high awareness of them. Only 11% of patients had written action plans, and one-half of patients with action plans did not use them regularly. Almost three-quarters of patients expressed concerns about taking inhaled corticosteroids. CONCLUSIONS Since the last major national survey, guideline implementation has not resulted in significant changes in asthma-related morbidity. Effective means of knowledge transfer should be developed and implemented to improve the translation of guideline recommendations into care.

Antibiotic Use in Children Is Associated With Increased Risk of Asthma

BACKGROUND. Antibiotic exposure in early childhood is a possible contributor to the increasing asthma prevalence in industrialized countries. Although a number of published studies have tested this hypothesis, the results have been conflicting. OBJECTIVE. To explore the association between antibiotic exposure before 1 year of age and development of childhood asthma. METHODS. Using administrative data, birth cohorts from 1997 to 2003 were evaluated (N = 251817). Antibiotic exposure was determined for the first year of life. After the first 24 months of life, the incidence of asthma was determined in both those exposed and not exposed to antibiotics in the first 12 months of life. Cox proportional hazards models were used to adjust for potential confounders and determine the hazard ratios associated with antibiotic exposure for the development of asthma. RESULTS. Antibiotic exposure in the first year of life was associated with a small risk of developing asthma in early childhood after adjusting for gender, socioeconomic status at birth, urban or rural address at birth, birth weight, gestational age, delivery method, frequency of physician visits, hospital visit involving surgery, visits to an allergist, respirologist, or immunologist, congenital anomalies, and presence of otitis media, acute, or chronic bronchitis, and upper and lower respiratory tract infections during the first year of life. As the number of courses of antibiotics increased, this was associated with increased asthma risk, with the highest risk being in children who received >4 courses. All antibiotics were associated with an increased risk of developing asthma, with the exception of sulfonamides. CONCLUSIONS. This study provides evidence that the use of antibiotics in the first year of life is associated with a small risk of developing asthma, and this risk increases with the number of courses of antibiotics prescribed.