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.
Salter B.M.,McMaster University |
Oliveria J.P.,McMaster University |
Nusca G.,McMaster University |
Smith S.G.,McMaster University |
And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015
Background Thymic stromal lymphopoietin (TSLP) released after antigenic stimulation of allergic asthmatic airways is a key initiator of type 2 inflammation. Basophils are important effectors of allergic inflammation in the airways. Murine basophils have been shown to respond to TSLP independently of IL-3 by increasing functional thymic stromal lymphopoietin receptor (TSLPR) expression. Objective The purpose of this study was to investigate the effect of TSLP stimulation on human basophil function. Methods Ten patients with mild allergic asthma underwent diluent and allergen inhalation challenges. Peripheral blood and sputum samples were collected at baseline and 7 and 24 hours after challenge, and bone marrow samples were collected at baseline and 24 hours after challenge to measure basophil TSLPR expression. In vitro experiments were conducted on purified human basophils to measure the effect of TSLP on degranulation, expression of activation markers and TH2 cytokines, and eotaxin-induced shape change. Results Allergen inhalation increased basophil numbers in the airways and significantly upregulated the expression of activation markers, TH2 intracellular cytokines, and receptors for TSLP, IL-3, and eotaxin in blood, bone marrow, and sputum basophils. In vitro stimulation with TSLP primed basophil migration to eotaxin and induced rapid and sustained basophil activation mediated directly through TSLPR and indirectly through an IL-3-mediated basophil autocrine loop. Basophils responded to TSLP at a similar magnitude and potency as the well-described basophil-activating stimuli IL-3 and anti-IgE. Conclusion Our findings indicate that basophil activation during early- and late-phase responses to inhaled allergen might be driven at least in part by TSLP. © 2015 American Academy of Allergy, Asthma & Immunology.
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.