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Title: Vitamin D and severe therapy resistant asthma in children
Author: Gupta, Atul
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Background There is increasing evidence that low vitamin D levels are implicated in paediatric asthma Hypotheses Children with severe, therapy resistant (STRA) have low serum vitamin D levels which are associated with worse asthma control and airway pathology. In vitro, steroid responsiveness of peripheral blood mononuclear cells (PBMCs) from STRA is improved by vitamin D. Methods Serum 25-hydroxyvitamin D (25[OH]D3) was measured in 36 STRA, 26 mild/moderate asthmatics (MA) and 24 non-asthmatic controls, and related to asthma control and exacerbations. 22/36 children with STRA underwent bronchoscopy with assessment of airway inflammation and remodelling. The in vitro steroid responsiveness of PBMC was assessed, in the absence or presence of dexamethasone and vitamin D. Results Median 25[OH]D3 levels were significantly lower in STRA (28nmol/L) than MA (42.5nmol/L) and controls (56.5nmol/L). There were positive relationships between 25[OH]D3 levels and %predicted first second forced expired volume (r=0.4, p<0.001) and forced vital capacity (r=0.3, p=0.002). 25[OH]D3 levels were positively associated with asthma control test (ACT) (r=0.6, p<0.001) and inversely associated with exacerbations (r=-0.6, p<0.001) and inhaled steroid dose (r=-0.39, p=0.001) in asthmatics. Airway smooth muscle (ASM) mass was inversely related to 25[OH]D3 levels (r=-0.6, p<0.01). Asthmatic children had diminished levels of bronchoalveolar lavage IL-10 (p<0.001). Their PBMC also demonstrated significantly impaired capacity to secrete IL-10 in culture (p<0.001) and the inclusion of vitamin D, enhanced dexamethasone-induced IL-10 (p<0.05), production. Furthermore vitamin D status correlated with airway IL-10 (r=0.6, p<0.01) and CD4+ FoxP3 T regulatory cells (r=0.6, p<0.01). Children with STRA had significantly higher vitamin D binding protein (VDBP) levels in BAL compared to MA (p<0.05) and controls (p<0.01) and these were positively associated with symptoms (ACT) (r=0.5, p=0.01) and inhaled corticosteroid usage (r=0.6, p=0<0.01). Summary Lower serum vitamin D levels in STRA children were associated with increased ASM mass, worse asthma control, lung function and reduced BAL IL-10 and T regulatory cells. In vitro vitamin D enhanced dexamethasone-induced IL-10 production. These data suggest vitamin D supplementation may be useful in STRA and support the need for a clinical trial.
Supervisor: Saglani, Sejal ; Bush, Andrew Sponsor: British Medical Association
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available