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)D(3)] 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 STRA (28 [22-38] nmol/L) than in MA (42.5 [29-63] 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 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). 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).

Conclusions: 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.

Figure 1

(A) Serum vitamin D levels in subjects with severe therapy-resistant asthma (STRA), subjects with moderate asthma (MA), and control subjects. Serum 25-hydroxyvitamin D levels were lower in subjects with STRA and subjects with MA than in control subjects (Kruskal-Wallis test, P < 0.0001). Horizontal bars represent median values. The Mann-Whitney U test, followed by a Bonferroni correction, was used to compare differences between groups. (B) A higher prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D levels less than 50 nmol/L) is shown in subjects with STRA compared with subjects with MA and control subjects (P < 0.001, calculated by chi-square test). ***P < 0.001.

Figure 2

Positive association between serum vitamin D levels and (A) percent predicted FEV₁ (R = 0.43, P < 0.001) and (B) FVC (R = 0.32, P = 0.002). Lower serum vitamin D levels were associated with (C) higher bronchodilator response (BDR) (r = −0.40, P = 0.003) and (D) positive BDR (FEV₁ improvement of at least 12%) (P < 0.001). BDR (%) = percentage increase in FEV₁ after inhalation of 1,000 μg of salbutamol. Correlation was determined by Spearman rank correlation coefficient. The Mann-Whitney U test was used to compare differences between groups. ***P < 0.001. MA = moderate asthma; STRA = severe therapy-resistant asthma.

Figure 3

Positive association between serum vitamin D level and asthma control test (ACT) (r = 0.6, P < 0.001). (A) Children with higher serum vitamin D levels had fewer asthma-related symptoms. Correlation was determined by Spearman rank correlation coefficient. (B) Children with lower serum vitamin D levels had more acute exacerbations in the last 6 months. Lower serum vitamin D levels were associated with increased (B) oral and (C) inhaled corticosteroid (ICS) use. The Kruskal-Wallis test and Mann-Whitney U test, followed by a Bonferroni correction, were used to compare differences between groups. **P < 0.01; ***P < 0.001. BDP = beclomethasone dipropionate; MA = moderate asthma; STRA = severe therapy-resistant asthma.

Figure 4

Relationships between serum 25-hydroxyvitamin D [25(OH)D₃] levels and airway remodeling. (A) There was a significant negative correlation between serum 25(OH)D₃ and volume fraction of airway smooth muscle (ASM) (r = −0.6, P = 0.008). There was no significant correlation between serum 25(OH)D₃ and (B) reticular basement membrane (RBM) thickness or (C) epithelial shedding. (D) There was no relationship between serum 25(OH)D₃ and proliferating cell nuclear antigen (PCNA)–positive smooth muscle cells. Correlation was determined by the Spearman rank correlation coefficient. Vv (sm/sm + submucosa) = volume fraction of smooth muscle indexed to volume of submucosal tissue PCNA SM cells per total SM cells; (%) = positively stained smooth muscle nuclei were counted in every biopsy at × 400 magnification and divided by the total number of smooth muscle nuclei and expressed as a percentage.

Figure 5

Relationship between volume fraction of airway smooth muscle (ASM) in endobronchial biopsies from children with severe therapy-resistant asthma (STRA), and asthma control test (ACT) and bronchodilator response (BDR). (A) A significant negative relationship was found between volume fraction of ASM and ACT (r = −0.7, P < 0.001). (B) A significant positive relationship was present between BDR and volume fraction of ASM (r = 0.6, P = 0.009). BDR (%) = percentage increase in FEV₁ after inhalation of 1,000 μg of salbutamol; Vv (sm/sm + submucosa) = volume fraction of smooth muscle indexed to volume of submucosa tissue.