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Title: Inflammatory phenotype and steroid responsiveness in children with severe asthma
Author: Bossley, Cara Jayne
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Introduction The pathology of paediatric severe therapy resistant asthma (STRA) and the mechanisms of steroid resistance are little studied. Hypotheses STRA is a T H2 driven eosinophilic disease and submucosal inflammation, specifically airway smooth muscle (ASM) eosinophil and mast cell infiltration predict steroid responsiveness Methods 52 STRA children, mean age 12.2 (6.5-17.3) years underwent an asthma control test (ACT), spirometry (forced expiratory volume in 1 second, FEV1), fractional exhaled nitric oxide at 50ml/sec (FeNO), sputum induction and bronchoscopy, bronchoalveolar lavage (BAL) and endobronchial biopsy (EB), and received a single dose of intramuscular triamcinolone. All tests (apart from bronchoscopy) were repeated 4 weeks later. Steroid response was assessed in four ways, (1) normalisation or improvement by ~ 50% in ACT, (2) normalisation or improvement of ~15% in FEV1. (3) normalisation of FeNO «24ppb) and (4) normalisation of sputum eosinophil % «2.5%). EB were assessed for inflammation and airway remodelling using image analysis. Luminex was used to quantify cytokines in sputum and BAL supernatants. In addition, 7 mild/moderate asthmatics (MA) and 16 controls underwent bronchoscopy, BAL and EB. Results STRA was eosinophilic, not neutrophilic as reported in adults. There was little evidence in sputum supernatant, BAL and EB of T H2 cytokines, with no significant difference between STRA, mild-moderate asthmatics and non-asthmatic controls. Steroid response was difficult to predict, but indicators of a poor response were atopy, eosinophilia (blood and EB), increased EB CD4+ count, ASM mast cells and RBM thickening. The adult criteria for steroid response were only applicable to 50% of STRA children. Conclusions Airway eosinophilia not neutrophilia predominates in childhood STRA. The mechanism of eosinophilia is obscure, and does not involve conventional signature T H2 cytokines, both findings in contrast to adult severe asthma. Thus therapies targeting T H2 cytokines may be inappropriate for the majority of children with STRA. A paediatric definition of steroid responsiveness needs to be developed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available