Relationship between Serum Vitamin D, Disease Severity, and Airway Remodeling in Children with Asthma

Abstract

Rationale-Little is known about vitamin D status and its effect on asthma pathophysiology in children with severe, therapy-resistant asthma (STRA).Objectives-Relationships between serum vitamin D, lung function, and pathology were investigated in pediatric STRA. Methods-Serum 25-hydroxyvitamin D [25(OH)D3 ] was measured in 86 children (mean age, 11.7 yr): 36 with STRA, 26 with moderate asthma (MA), and 24 without asthma (control subjects). Relationships between 25(OH)D 3 , the asthma control test (ACT), spirometry, corticosteroid use, and exacerbations were assessed. Twenty-two of 36 children with STRA underwent fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy with assessment of airway inflammation and remodeling. Measurements and Main Results-25(OH)D 3 levels (median [IQR]) were significantly lower in nmol/L) than in nmol/L) and control subjects (56.5 [45-67] nmol/L) (P < 0.001). There was a positive relationship between 25(OH)D 3 levels and percent predicted FEV 1 (r = 0.4, P < 0.001) and FVC (r = 0.3, P = 0.002) in all subjects. 25(OH)D 3 levels were positively associated with 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 MA and and STRA. Airway smooth muscle (ASM) mass, but not epithelial shedding or reticular basement membrane thickness, was inversely related to 25(OH)D 3 levels (r=−0.6, P = 0.008). Copyright © 2011 by the American Thoracic SocietyCorrespondence and requests for reprints should be addressed to Atul Gupta, M.D., Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. atulgupta@doctors.org.uk. Author Contributions: A.G. recruited the majority of the patients, collected patient samples, conducted the majority of the experiments, analyzed the data, and took the lead on writing the manuscript. A.S. performed some of the experimental work. A.G., A.B., C.H., and S.S. conceptualized, delineated the hypotheses, and designed the experiments A.B., C.H., D.R., and S.S. contributed to the interpretation of the analyses, supervised the project, and helped with revising the manuscript. A.B. and S.S. also performed bronchoscopies and obtained samples. W.B. performed some of the statistical analyses. There was a positive correlation between ASM mass and bronchodilator reversibility (r = 0.6, P = 0.009) and an inverse correlation between ASM mass and ACT (r = −0.7, P < 0.001). Author DisclosuresConclusions-Lower vitamin D levels in children with STRA were associated with increased ASM mass and worse asthma control and lung function. The link between vitamin D, airway structure, and function suggests vitamin D supplementation may be useful in pediatric STRA. Keywordsvitamin D; asthma; remodeling; airway smooth muscle; pediatrics For most children with ready access to healthcare, asthma can be controlled with low doses of inhaled steroids. There remains, however, a significant number of individuals with asthma who, despite apparentl...

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

“…Our own studies have addressed this in a severe therapy-resistant pediatric asthma cohort. We observe highly significant associations between serum 25-hydroxyvitamin D3 levels with lung function, asthma severity, and control [21]. Using this unique patient cohort, we recorded a positive correlation between serum 25-hydroxyvitamin D3 levels with the frequency of CD25 + Foxp3 + T cells in the airways, complimenting our in vitro observations.…”

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

“…Several studies have pointed out striking links in populations between vitamin D deficiency and asthma severity or requirements for anti-inflammatory medication (27)(28)(29)(30). In previous studies investigating the immunological basis of this relationship, we have shown that 1 α,25-dihydroxyvitamin D3…”

“…This arises in part from studies demonstrating that patients with poorly controlled asthma and/or poor responsiveness to corticosteroid have significantly reduced vitamin D, at least as assessed by the circulating precursor 25-hydroxyvitamin D3 (27)(28)(29)(30)47). We and others have previously demonstrated an association with 25(OH)2D3 status and airways smooth muscle mass (27,28,48). Bronchial smooth muscle hypertrophy and hyperplasia are prominent features of airway remodelling as is subepithelial fibrosis, and IL-17A is a key mediator implicated in lung structural changes with pro-fibrotic activity within the bronchial epithelium (45).…”

Serum 25-hydroxyvitamin D levels do not correlate with asthma severity in a case-controlled study of children and adolescents

“…This study, however, showed a significant inverse association between vitamin D and serum IgE, as well as vitamin D and daily inhaled corticosteroid dose in the pedia tric asthma group only (17) . Among the non casecontrol studies that reported significant inverse correlation with asthma severity, one study evaluated 616 asthmatic patients (13) , another studied 75 asthmatic patients (14) , whereas a third study investigated 86 asthmatic patients (16) . Therefore, more carefully designed studies are needed to clarify the relationship between asthma seve rity and vitamin D status.…”

“…Another study from northern Italy showed a direct correlation between asthma control and serum 25(OH)D in a cohort of asthmatic children (14) . Other cross-sectional studies in children have shown that serum 25(OH)D concentrations are directly correlated with pulmonary function parameters, such as forced expiratory volume in one second (15) , and also inversely correlated with asthma severity and airway smooth muscle mass (16) .…”