Firestone Institute for Respiratory Health

Hamilton, Canada

Firestone Institute for Respiratory Health

Hamilton, Canada
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ATS 2017, WASHINGTON, DC-- An investigational biologic may reduce the need for adults with severe asthma to take an oral corticosteroid to control their asthma, according to a randomized controlled trial presented at the ATS 2017 International Conference. Study findings are being reported simultaneously online, ahead of print in the New England Journal of Medicine. The biologic is benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, that when delivered subcutaneously, rapidly depletes eosinophils, cells that at high concentrations in the blood and airways lead to frequent asthma exacerbations. Benralizumab was evaluated for patients whose asthma is not well-controlled by high dosages of the standard therapies of inhaled corticosteroids and long-acting β2-agonists and, therefore, were prescribed an add-on oral corticosteroid (prednisone) on a regular basis to boost control. "Frequent or long-term use of systemic corticosteroids can lead to potentially life-threatening complications, including osteoporosis, diabetes, cardiovascular disease and adrenal suppression," said lead author Parameswaran Nair, MD, PhD, professor of medicine at the Firestone Institute for Respiratory Health, at McMaster University in Hamilton, Canada. "We need new, safe therapies that would replace the need for systemic corticosteroids for patients with severe asthma." According to the authors, about 5 to 10 percent of people with asthma have a severe form of the disease, and studies have shown that 32 to 45 percent of these people require frequent or maintenance oral corticosteroids. In this double-blinded, Phase 3 trial, known as ZONDA (named for the dry, warm Andean wind), 220 patients, age 18 to 75, were randomized into three arms: those receiving benralizumab every four weeks, those receiving benralizumab every eight weeks (after three initial four-week doses), and those receiving a placebo. At the end of 28 weeks, the investigators found: The researchers said that approximately 20 percent of patients did not respond to benralizumab and that future studies would be needed to determine which patients would benefit from the biologic. "It is possible that these patients' asthma was not critically dependent on the eosinophils, or they may not have had significant airway eosinophil activity," Dr. Nair said, adding that "longer term studies of patients with prednisone-dependent asthma are needed before definitive conclusions can be drawn about the long-term efficacy and safety of benralizumab and eosinophil depletion." Benralizumab is under regulatory review in the United States, European Union, Japan and several other countries. The study was funded by AstraZeneca. Benralizumab Significantly Reduced Oral Corticosteroid Dosages and Asthma Exacerbation Rates for Patients with Severe, Uncontrolled Asthma: Results of the ZONDA Phase III Trial Authors: P. Nair1, S.E. Wenzel2, K.-F. Rabe3, A. Bourdin4, N. Lugogo5, P. Kuna6, P. Barker7, S. Sproule7, S. Ponnarambil8, M. Goldman7; 1McMaster University & St Joseph's Healthcare - Hamilton, ON/CA, 2University of Pittsburgh - Pittsburgh, PA/US, 3Lungen-Clinic Großhansdorf - Großhansdorf/DE, 4Hôpital Arnaud de Villeneuve- Montpellier/FR, 5Duke University Medical Center - Durham, NC/US, 6Barlicki University Hospital, Medical University of ?ód? - ?ód?/PL, 7AstraZeneca - Gaithersburg, MD/US, 8AstraZeneca - Cambridge/GB; on behalf of the ZONDA study investigators Rationale: Patients with uncontrolled asthma despite high-dosage inhaled corticosteroids plus long-acting β2-agonists (ICS/LABA) may need add-on oral corticosteroid (OCS) treatment to manage symptoms. However, frequent OCS use is associated with adverse effects. Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. In Phase III trials,1,2 benralizumab significantly reduced annual exacerbation rates for patients with severe, eosinophilic asthma. The ZONDA trial (NCT02075255) evaluated OCS dosage-sparing effects of benralizumab for patients with severe asthma receiving high-dosage ICS/LABA and OCS. Methods: In this RCT, 271 patients (aged 18-75 years) with severe, uncontrolled asthma (eosinophil counts ?150 cells/μL) receiving high-dosage ICS/LABA and OCS (7.5-40 mg/d) entered an initial 2- to 8-week run-in/optimization period during which their OCS dosage was titrated to the minimum effective dosage (baseline) without losing asthma control. Eligible patients were then randomized 1:1:1 to three 28-week treatment groups: benralizumab 30 mg SC either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo SC every 4 weeks. The treatment period comprised a 4-week induction phase (optimized OCS dosage maintained), a 20-week reduction phase (OCS dosage reduced), and a final 4-week maintenance phase (no further OCS dosage adjustment). Primary efficacy endpoint was percentage reduction from baseline in final OCS dosage while maintaining asthma control at Week 28. Annual asthma exacerbation rate was a secondary endpoint. Each benralizumab regimen was compared with placebo. Results: Of 220 patients who were randomized and received treatment, 207 (94.1%) completed treatment. Benralizumab significantly reduced final OCS dosages by a median of 75% with the Q4W and Q8W regimens (p Percentage reduction from baseline in daily OCS dosage at Week 28 HL estimate (95% CI) for median difference vs. placebo, %c No change or any increase in dosage All randomized patients who received any study treatment. bFinal daily oral corticosteroid (OCS) dosage was the dosage at Week 28. If a patient discontinued from the study during a given dosage reduction interval or a patient experienced an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dosage was one dose level greater than that directly preceding the event. cThe Hodges-Lehmann (HL) estimate and 95% confidence intervals (CIs) were the median for the n1 X n2 differences between treatment groups, where n1 was the number of patients in each benralizumab-treated group and n2 was the number of patients receiving placebo. dCumulative percentage reductions. Patients with baseline OCS dosage ?12.5 mg/d were eligible for 100% dosage reductions. eThe proportional odds model was a sensitivity analysis and was not multiplicity protected. Estimate of the proportional odds ratio (OR) for the two treatment groups compared with the placebo group used a proportional odds model, with control for treatment group, region, and baseline OCS dosage. fEstimates via a negative binomial model, with adjustment for treatment group, region, and number of exacerbations in the previous year.


Hancox R.J.,University of Otago | Subbarao P.,Hospital for Sick Children | Sears M.R.,Firestone Institute for Respiratory Health
Current Allergy and Asthma Reports | Year: 2012

The definition of persistent asthma in longitudinal studies reflects symptoms reported at every assessment with no substantive asymptomatic periods. Early-childhood wheezing may be transient, especially if it is of viral etiology. Longitudinal studies provide greater opportunity to confirm the diagnosis by variability of symptoms, objective measurements, and therapeutic responses. Several clinical phenotypes of childhood asthma have been identified, with general consistency between cohorts. Persistent wheezing is often associated with loss of lung function, which is evident from early-childhood and related to persistent inflammation and airway hyperresponsiveness. Female sex, atopy, airway responsiveness, and personal smoking, but not exposure to environmental tobacco smoke, are risk factors for persistence of childhood asthma into adulthood. The effect of breastfeeding remains controversial, but gene-environment interactions may partly explain outcomes. Understanding the natural history and underlying causes of asthma may lead to development of strategies for primary prevention. © Springer Science+Business Media, LLC 2012.


Farkas L.,McMaster University | Farkas L.,Firestone Institute for Respiratory Health | Farkas L.,Virginia Commonwealth University | Gauldie J.,McMaster University | And 3 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2011

Idiopathic pulmonary fibrosis (IPF) is a disabling disease of the lung parenchyma, characterized by progressive accumulation of scar tissue and myofibroblast activation after repetitive epithelial microinjury. The therapeutic options are limited, and patients usually die within a few years after diagnosis. Pulmonary hypertension (PH) in IPF has been increasingly recognized as a condition with relevance for the overall prognosis. Treatment trials are being designed, but to be effective, it is crucial to better understand the pathobiology of PH in IPF: the traditional concept, that hypoxic vasoconstriction and accumulation of scar tissue are mainly responsible for the development of PH in IPF, has been challenged. Recent studies, including our own in vivo research, suggest that the underlying pathobiology is much more complex, and includes a complicated interaction of epithelial cells, fibroblasts, and vascular cells. This interaction seems to be regulated by a large variety of angiogenesis promoters and inhibitors, as well as growth factors. Central components seem to be endothelial apoptosis and growth factor-induced remodeling of the pulmonary artery wall. The present review gives a conceptual overview about known and putative mechanisms that are involved in the development of PH in IPF. This report summarizes currently available therapeutic options, and also translates experimental research to discuss potential novel biomarkers and therapeutic strategies derived from new concepts in pathogenesis.


Nair P.,Firestone Institute for Respiratory Health | Hargreave F.E.,McMaster University
Chest | Year: 2010

Airway inflammation is fundamental to the cause and persistence of asthma and other airway conditions. It contributes to symptoms, variable airflow limitation, airway hyperresponsiveness, and the structural changes (remodeling) associated with asthma. However, the presence and type of airway inflammation can be difficult to detect clinically, delaying the introduction of appropriate treatment. Cellular inflammation in the airway can be accurately and reliably assessed by examining spontaneous or, when not available, induced sputum. Induced sputum cell counts are relatively noninvasive, safe, and reliable. They can accurately discriminate eosinophilic airway inflammation from noneosinophilic airway inflammation and, thus, help to guide therapy. Eosinophilic airway inflammation is steroid responsive, whereas noneosinophilic (usually neutrophilic) inflammation generally is not. Monitoring of airway inflammation using sputum cell counts helps to identify the impending loss of asthma control and, thus, the need to adjust antiinflammatory medications in patients with a variety of airway diseases, such as asthma, smoker's COPD, and chronic cough. Other noninvasive, indirect measurements of airway inflammation, such as exhaled nitric oxide, do not help to identify the cellular nature of airway inflammation associated with exacerbations of airway diseases, particularly in patients who are already on corticosteroids. Thus, although they can be a predictor of steroid responsiveness, these measures do not help to reduce asthma exacerbations when used in clinical practice. The clinical usefulness of measurements in exhaled breath condensate has not yet been established. © 2010 American College of Chest Physicians.


Sears M.R.,McMaster University | Sears M.R.,Firestone Institute for Respiratory Health
Chest | Year: 2014

The asthma epidemic of the last few decades may have peaked; studies suggest that the incidence and prevalence of asthma has decreased in some countries in the last few years, although other studies suggest continuing small increases in prevalence. Increasing awareness and changing diagnostic habits make precise evaluation of epidemiologic trends diffi cult in the absence of a gold-standard test for asthma, and on a global basis uncertainty persists. Trends in prevalence in some populations (eg, immigrants, farming communities) suggest both adverse and benefi cial effects of specifi c environmental factors. Although the effects of indoor allergens, dampness, and mold and of outdoor air pollutants, especially traffi c related, have traditionally dominated riskfactor research, more recent epidemiologic and clinical studies have focused on metabolic and nutritional factors, including maternal obesity and vitamin D levels, mode of delivery and its effect on the infant microbiome, fetal and infant growth, the psychosocial environment, and medication use by mother and infant. It is likely that changes in incidence and prevalence are due to multiple factors, each contributing a relatively small effect. Longitudinal studies from pregnancy through childhood to adulthood will yield greater insights into the complex pathways leading to asthma. © 2014 American College of Chest Physicians.


O'Byrne P.M.,Firestone Institute for Respiratory Health | O'Byrne P.M.,McMaster University
Journal of Allergy and Clinical Immunology | Year: 2011

Asthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled β2-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled β2-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled β2- agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti-IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations. © 2011 American Academy of Allergy, Asthma & Immunology.


Cox G.,Firestone Institute for Respiratory Health
Current Opinion in Pulmonary Medicine | Year: 2011

Purpose of review: The present article will address the potential for bronchial thermoplasty to be used in addition to conventional medications to help us treat our patients with severe asthma. Recent findings: Two recently published studies report on the use of bronchial thermoplasty in patients with severe asthma. Now that patients with a range of asthma severity have been treated with bronchial thermoplasty, we are better able to comment on the appropriate selection of patients for this therapy that should optimize benefits and limit complications. In addition, studies reporting longer term follow-up are now available indicating the persistence of benefit and the absence of late developing adverse events. Summary: Bronchial thermoplasty represents a novel approach to asthma treatment that is complementary to anti-inflammatory and bronchodilating therapies. Criteria for selecting appropriate patients are established and experience with bronchial thermoplasty is expanding since US Food and Drug Administration approval was obtained in April 2010. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Nair P.,Firestone Institute for Respiratory Health
Cochrane database of systematic reviews (Online) | Year: 2012

Asthma is a chronic condition in which sufferers may have occasional or frequent exacerbations resulting in visits to the emergency department (ED). Aminophylline has been used extensively to treat exacerbations in acute asthma settings; however, it's role is unclear especially with respect to any additional benefit when added to inhaled beta(2)-agonists. To determine the magnitude of effect of the addition of intravenous aminophylline to inhaled beta(2)-agonists in adult patients with acute asthma treated in the ED setting. We identified trials from the Cochrane Airways Group register (derived from MEDLINE, EMBASE, CINAHL standardised searches) and handsearched respiratory journals and meeting abstracts. Two independent review authors screened and obtained potentially relevant articles and handsearched their bibliographic lists for additional articles. In the original version of this review published in 2000 we included searches of the database up to 1999. The 2012 review was updated with a revised search from inception to September 2012. Randomised controlled trials comparing intravenous aminophylline versus placebo in adults with acute asthma and treated with inhaled beta(2)-agonists. We included patients who were treated with or without corticosteroids or other bronchodilators provided this was not part of the randomised treatment. Two review authors independently extracted data and one review author entered data into RevMan, which was checked by a second review author. Results are reported as mean differences (MD) or odds ratios (OR) with 95% confidential intervals (CI). Fifteen studies were included in the previous version of the review, and we included two new studies in this update, although we were unable to pool new data. Overall, the quality of the studies was moderate; concealment of allocation was assessed as clearly adequate in only seven (45%) of the trials. There was significant clinical heterogeneity between studies as the doses of aminophylline and other medications and the severity of the acute asthma varied between studies.There was no statistically significant advantage when adding intravenous aminophylline with respect to hospital admissions (OR 0.58; 95% CI 0.30 to 1.12; 6 studies; n = 315). In 2000 it was found that there was no statistically significant effect of aminophylline on airflow outcomes at any time period; the addition of two trials in 2012 has not challenged this conclusion. People treated with aminophylline and beta(2)-agonists had similar peak expiratory flow (PEF) values compared to those treated with beta(2)-agonists alone at 12 h (MD 8.30 L/min; 95% CI -20.69 to 37.29 L/min) or (MD -1.21% predicted; 95% CI -14.21% to 11.78% predicted) and 24 h (MD 22.20 L/min; 95% CI -56.65 to 101.05 L/min). Two subgroup analyses were performed by grouping studies according to mean baseline airflow limitation (11 studies) and the use of any corticosteroids (nine studies). There was no relationship between baseline airflow limitation or the use of corticosteroids on the effect of aminophylline. Aminophylline-treated patients reported more palpitations/arrhythmias (OR 3.02; 95% CI 1.15 to 7.90; 6 studies; n = 249) and vomiting (OR 4.21; 95% CI 2.20 to 8.07; 7 studies; n = 321); however, no significant difference was found in tremor (OR 2.60; 95% CI 0.62 to 11.02; 5 studies; n = 249). The use of intravenous aminophylline did not result in significant additional bronchodilation compared to standard care with inhaled beta(2)-agonists in patients experiencing an asthma exacerbation in the ED setting, or in a significant reduction in the risk of hospital admission. For every 100 people treated with aminophylline an additional 20 people had vomiting and 15 people arrhythmias or palpitations. No subgroups in which aminophylline might be more effective were identified. Our update in 2012 is consistent with the original conclusions that the risk-benefit balance of intravenous aminophylline is unfavourable.


Nair P.,Firestone Institute for Respiratory Health | Aziz-Ur-rehman A.,Firestone Institute for Respiratory Health | Radford K.,Firestone Institute for Respiratory Health
Current Opinion in Pulmonary Medicine | Year: 2015

Purpose of review This review examines the association between airway neutrophilia and severe asthma, potential mechanisms, and the effect on asthma control of therapies directed at reducing airway neutrophil numbers or activity.Recent findings The majority of studies that observe an association between airway neutrophilia and severe asthma are cross-sectional in nature, and the intensity of neutrophilia is low and may be a reflection of the age of the patients, effect of tobacco smoke exposure, or the high doses of corticosteroids used to treat their asthma. There may be a small proportion of patients who may have abnormal innate immune responses that may lead to airway neutrophilia. However, these neutrophils may not be any more activated than in patients with milder asthma. Novel strategies using small molecule antagonists against the interleukin-8 receptor, CXCR2, are able to reduce airway neutrophilia, and their clinical efficacies are being investigated.Summary Although cross-sectional studies suggest that airway neutrophilia may be observed in some patients with severe asthma, it is not clearly established if this is a consequence of treatment with corticosteroids or if it contributes directly to asthma pathobiology and severity. New therapies such as anti-CXCR2 provide an opportunity to investigate the contribution of neutrophils to asthma severity. © 2014 Wolters Kluwer Health.


Cox G.,Firestone Institute for Respiratory Health
Clinics in Chest Medicine | Year: 2010

Asthma, by definition is a variable disease. When there is more than normal natural variation in airflow, asthma can be provoked by a wide range of stimuli that include infectious, allergic, and environmental agents. Bronchoconstriction determines much of the short-term variability in airflow that characterizes asthma. Current treatments do not redress the excess smooth muscle mass that is present in the remodeled airway in chronic asthma. Thus, it is intriguing to consider the potential contribution of bronchial thermoplasty (a procedure that involves controlled heat treatment to reduce the mass of the airway smooth muscle) as an effective therapy for poorly controlled asthma. © 2010 Elsevier Inc. All rights reserved.

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