Asthma: Defining of the persistent adult phenotypes
Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA. The Lancet
(Impact Factor: 45.22).
09/2006; 368(9537):804-13. DOI: 10.1016/S0140-6736(06)69290-8
The common disease asthma is probably not a single disease, but rather a complex of multiple, separate syndromes that overlap. Although clinicians have recognised these different phenotypes for many years, they have remained poorly characterised, with little known about the underlying pathobiology contributing to them. Development of targeted therapies for asthma, and phenotype-specific clinical trials have raised interest in these phenotypes. Improved understanding of these phenotypes in complex diseases such as asthma will also improve our ability to link specific genotypes to their associated disease, which should help development of biomarkers. However, there is no standardised method to define asthma phenotypes. This Review analyses some of the methods that have been used to define asthma phenotypes and proposes an integrated method of classification to improve our understanding of these phenotypes.
Available from: Greg Mullen
- "Asthma is a complex, heterogeneous and chronic inflammatory lung disease characterised by reversible bronchoconstriction, airway inflammation and hyperresponsiveness (Lemanske and Busse, 2010). Differential net infiltration of effector granulocytes, particularly eosinophils and neutrophils into the airways forms the basis of current definitions of asthma phenotypes and endotypes (Wenzel, 2006; Simpson et al., 2006). There remains controversy, however, as to the precise mechanism of genesis of such phenotypes (Cieslewicz et al., 1999). "
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It is important to study differential inflammatory cellular migration, particularly of eosinophils and neutrophils, in asthma and how this is influenced by environmental stimuli such as allergen exposure and the effects of anti asthma therapy.
We isolated blood neutrophils and eosinophils from 12 atopic asthmatic human volunteers (Group 1 — four Early Allergic Responders unchallenged (EAR); Group 2 — four Early and Late Allergic Responders (LAR) challenged; Group 3 — four EAR and LAR challenged and treated with systemic corticosteroids) using cGMP CD16 CliniMACS. Cells were isolated prior to allergen challenge where applicable, labelled with 99mTc-HMPAO and then re-infused intravenously. The kinetics of cellular influx/efflux into the lungs and other organs were imaged via scintigraphy over 4 h, starting at 5 to 6 h following allergen challenge where applicable.
Neutrophils and eosinophils were isolated to a mean (SD) purity of 98.36% (1.09) and 96.31% (3.0), respectively. Asthmatic neutrophils were activated at baseline, mean (SD) CD11bHigh cells 46 (10.50) %. Isolation and radiolabelling significantly increased their activation to > 98%. Eosinophils were not activated at baseline, CD69+ cells 1.9 (0.6) %, increasing to 38 (3.46) % following isolation and labelling. Analysis of the kinetics of net eosinophil and neutrophil lung influx/efflux conformed to a net exponential clearance with respective mean half times of clearance 6.98 (2.18) and 14.01 (2.63) minutes for Group 1, 6.03 (0.72) and 16.04 (2.0) minutes for Group 2 and 5.63 (1.20) and 14.56 (3.36) minutes for Group 3. These did not significantly differ between the three asthma groups (p > 0.05).
Isolation and radiolabelling significantly increased activation of eosinophils (CD69) and completely activated neutrophils (CD11bHigh) in all asthma groups. Net lung neutrophil efflux was significantly slower than that of eosinophils in all asthma study groups. There was a trend for pre-treatment with systemic corticosteroids to reduce lung retention of eosinophils following allergen challenge.
10/2014; 1(1). DOI:10.1016/j.ebiom.2014.10.014
Available from: Shyamali Chandrika Dharmage
- "An area that needs research is the current classifications for obstructive lung diseases. These classifications are complex, with asthma regarded as multiple overlapping syndromes,174 and the heterogeneity of both stable COPD and its acute exacerbations being increasingly recognized.133 The GOLD strategy document has progressively acknowledged the overlap between asthma and COPD, and progress is being made on a joint Global Initiative for Asthma/GOLD asthma–COPD overlap document. "
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ABSTRACT: Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are major public health burdens. This review presents a comprehensive synopsis of their epidemiology, pathophysiology, and clinical presentations; describes how they can be distinguished; and considers both established and proposed new approaches to their management. Both adult-onset asthma and COPD are complex diseases arising from gene-environment interactions. Early life exposures such as childhood infections, smoke, obesity, and allergy influence adult-onset asthma. While the established environmental risk factors for COPD are adult tobacco and biomass smoke, there is emerging evidence that some childhood exposures such as maternal smoking and infections may cause COPD. Asthma has been characterized predominantly by Type 2 helper T cell (Th2) cytokine-mediated eosinophilic airway inflammation associated with airway hyperresponsiveness. In established COPD, the inflammatory cell infiltrate in small airways comprises predominantly neutrophils and cytotoxic T cells (CD8 positive lymphocytes). Parenchymal destruction (emphysema) in COPD is associated with loss of lung tissue elasticity, and small airways collapse during exhalation. The precise definition of chronic airflow limitation is affected by age; a fixed cut-off of forced expiratory volume in 1 second/forced vital capacity leads to overdiagnosis of COPD in the elderly. Traditional approaches to distinguishing between asthma and COPD have highlighted age of onset, variability of symptoms, reversibility of airflow limitation, and atopy. Each of these is associated with error due to overlap and convergence of clinical characteristics. The management of chronic stable asthma and COPD is similarly convergent. New approaches to the management of obstructive airway diseases in adults have been proposed based on inflammometry and also multidimensional assessment, which focuses on the four domains of the airways, comorbidity, self-management, and risk factors. Short-acting beta-agonists provide effective symptom relief in airway diseases. Inhalers combining a long-acting beta-agonist and corticosteroid are now widely used for both asthma and COPD. Written action plans are a cornerstone of asthma management although evidence for self-management in COPD is less compelling. The current management of chronic asthma in adults is based on achieving and maintaining control through step-up and step-down approaches, but further trials of back-titration in COPD are required before a similar approach can be endorsed. Long-acting inhaled anticholinergic medications are particularly useful in COPD. Other distinctive features of management include pulmonary rehabilitation, home oxygen, and end of life care.
International Journal of COPD 09/2014; 9:945-962. DOI:10.2147/COPD.S46761 · 3.14 Impact Factor
Available from: César Picado
- "Classification of phenotypes is based empirically on the principle that similarity measured across a number of different characteristics may predict relationships of biological significance with greater probability. Cluster analysis refers to a group of multivariate mathematical algorithms that, broadly, quantify similarity between individuals and group individuals into clusters such that similarity between members of the same clusters is strong.16,17 "
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ABSTRACT: Intrinsic asthma has been considered as a specific disease entity for a long time, although many controversies have emerged in relation to this concept. Of note, not finding specific allergen sensitization in an asthmatic patient neither excludes an allergic component nor the essential role that immunoglobulin E may play in asthma. The diagnostic approach should be similar in any patient suspected to have asthma. The atopic status is one among many other questions. Omalizumab, the only monoclonal anti-immunoglobulin E antibody commercialized for asthma, should be tried in patients with uncontrolled severe asthma independent of their atopic status.
International Journal of General Medicine 07/2014; 7:365-71. DOI:10.2147/IJGM.S45259
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