Vitamin D and Asthma: Association, Causality, or Intervention?

Abstract

Many observational studies have investigated the potential association between vitamin D and asthma. However, it is difficult to find a temporal causal relationship in cross-sectional or observational studies. This review presents recent clinical trials and the evidence of association between vitamin D and asthma in different patient populations and asthma status. Well-designed clinical trials are warranted in order to define the optimal level of vitamin D, as well as dosing and duration of vitamin D supplementation, in pediatric patients.

There has been an increase in the number of publications investigating the association between vitamin D and many diseases, including asthma. The relationship between vitamin D and asthma can be explored in several ways: potential role in primary prevention, improvement of lung function, protection against or reduction of asthma morbidity, and enhancement of clinical response to corticosteroids. Upon review of the recent data, it is important to note that vitamin D deficiency or insufficiency, as measured by 25-hydroxyvitamin D (25-OH-VitD) in the serum, has been defined differently across the various trials. The optimal level of 25-OH-VitD for nonmusculoskeletal conditions and for different ethnicities remains controversial and unclear.¹ The Institute of Medicine recommends at least 20 ng/mL of 25-OH-VitD for the maintenance of bone health.²

Vitamin D concentration during pregnancy and risk of developing pulmonary diseases has been a topic of discussion. The results of studies measuring maternal vitamin D or cord blood at the time of delivery have provided conflicting results, from inverse to positive associations with risk of childhood wheezing or developing childhood asthma.³

In a large longitudinal study of children in Australia,⁴ the association between vitamin D status at 6 years of age and development of asthma at 14 years of age was investigated in 693 children in a subgroup analysis. The authors reported a predictive association between vitamin D at age 6 and asthma at age 14 years; the association was essentially confined to males when the data were stratified for sex. A birth cohort study in the Netherlands⁵ reported the cross-sectional and prospective associations between vitamin D status and prevalence of asthma in childhood. Data were available for a subgroup of 4 year olds (n=72) and a subgroup of 8 year olds (n=328). Interestingly, vitamin D concentration at 4 years of age was inversely associated with asthma at 4–8 years of age. However, vitamin D at 8 years of age was positively associated with asthma at the same age. The association between vitamin D status early on and the risk for developing asthma in school age children remains unclear.

Several similar epidemiologic studies suggest an inverse association between vitamin D concentration and asthma-related outcomes.^6,7 In a cross-sectional study of 100 patients aged between 0 and 18 years of age with asthma, 47% had insufficient vitamin D concentrations defined as <30 ng/mL.⁸ Use of oral and inhaled corticosteroids taken over 30 days before the vitamin D measurement showed a significant inverse relationship with vitamin D. A significant positive correlation was reported between forced expiratory volume in first second (FEV1) percent predicted and FEV1/forced vital capacity (FVC) with vitamin D level. These results suggest that vitamin D insufficiency may be a cause of greater need for therapy in patients with asthma.

The association between vitamin D status and severe asthma exacerbations was evaluated in the Childhood Asthma Management Program (CAMP) study where 25-OH-Vit D concentrations were collected from 1,024 in children 5–12 years of age with mild to moderate persistent asthma at the time of the enrollment.^9,10 Patients were randomly assigned to budesonide, nedocromil, or placebo, and were followed for a mean of 4.3 years. For the purpose of this analysis, severe asthma exacerbation was defined as any emergency department (ED) visit or hospitalization for asthma during the study. Vitamin D insufficiency was defined as 25-OH-VitD <30 ng/mL. Thirty-five percent of children were vitamin D insufficient. Adjusted for age, sex, body mass index, income, and treatment group, the odds of any ED visits or hospitalizations due to asthma was significantly higher in the vitamin D insufficient children over the 4 years of the CAMP trial (odds ratio 1.5 [95% confidence interval 1.1–1.9], p=0.01). The association between vitamin D insufficiency and severe asthma exacerbation was also evaluated in a year before the study enrollment, and the odds ratio remained significantly higher in the vitamin D insufficient children. There were no significant differences in skin test reactivity, eosinophils count, or total serum IgE levels between the vitamin D sufficient and insufficient children. There was also no difference in the odds of having prednisone bursts during the 4 years of the CAMP trial. These results suggest that sufficient vitamin D may not prevent exacerbations but it may decrease the severity of exacerbations, hence reducing ED visits or hospitalization due to asthma.

In a recent publication, vitamin D deficiency was investigated as a risk factor for exacerbations of wheezing episodes in preschool children. A post hoc analysis was done in a well-defined cohort of preschool children with severe intermittent asthma.^11,12 The details of the original study and primary outcomes have been discussed previously.¹³ Briefly, in this multicenter, double-blind, randomized clinical trial, 264 children 12–53 months old were randomly assigned to daily low-dose budesonide inhalation suspension or intermittent use of high-dose budesonide inhalation suspension at the early signs of a respiratory tract illness.¹¹ Patients were followed for 1 year, and the primary outcome was asthma exacerbation requiring use of oral corticosteroids. Vitamin D status was assessed in 95% of the patients at baseline, and vitamin D deficiency was defined as 25-OH-VitD <20 ng/mL.¹² There was a significantly higher rate of exacerbation in patients with vitamin D deficiency compared to those with sufficient vitamin D (1.46 vs. 0.93 exacerbation/child-year, p=0.035). Secondary outcomes of episode-free days, rate of respiratory tract illness, and rate of ED or urgent care visits did not differ between the vitamin D deficient and sufficient groups.

The effect of vitamin D deficiency on the treatment of asthma has also been investigated. In the CAMP trial, the effect of vitamin D and treatment with budesonide on prebronchodilator FEV1, bronchodilator response to inhaled β-agonist (BDR), and provocative concentration of methacholine producing a 20% decline in FEV1 (PC20) over the first 8–12 months of the study was evaluated.¹⁴ This duration was chosen, since the maximum effect of inhaled corticosteroid (ICS) on BDR was observed at the first 12 months of the CAMP study. Treatment with ICS was associated with a significantly greater change in prebronchodilator FEV1 and FEV1 percent predicted in children with sufficient (>30 ng/mL) or insufficient (20–30 ng/mL) vitamin D compared to deficient (<20 ng/mL) vitamin D children (least squares regression, adjusted for age, race, sex, BMI, history of ED visit, and season when vitamin D was measured, p=0.0072 and p=0.036 respectively). Although the change in BDR decreased in both sufficient and insufficient vitamin D children and increased in vitamin D deficient children, the association was not significant. There was no significant association between the outcomes, vitamin D status, and placebo or nedocromil treatment arms. The authors concluded that sufficient vitamin D level in conjunction with ICS is associated with improved lung function, indicating that vitamin D may enhance the anti-inflammatory effect of ICS in children with asthma. Similar results were reported in a cross-sectional study of adult patients with asthma.¹⁵ A significant correlation was shown between FEV1 and vitamin D concentration in 54 asthmatic patients (p=0.02, r=0.8) with a stronger association between ICS untreated patients compared to those who were treated with ICS.

Vitamin D concentration and the effect of corticosteroids on bone mineral density (BMD) in children with asthma have been investigated. Bone mineral accretion (BMA) and vitamin D status were evaluated in 780 children in the CAMP cohort.¹⁶ Boys with insufficient vitamin D had more than twice the decrease in BMA with exposure to more than two courses of oral corticosteroids per year compared to those with sufficient vitamin D status (p<0.001). This effect was associated with a risk of osteopenia but not fracture. The result suggests a possible means of minimizing the effect of corticosteroids on bone metabolism. In a randomized, double-blind study in adult patients with mild to moderate asthma, patients were randomly assigned to daily doses of mometasone furoate 400 μg or 200 μg, fluticasone propionate 500 μg or montelukast 10 mg for 1 year.¹⁷ All patients had 25-OH-Vit D concentrations >15 ng/mL at baseline and continued a daily dose of 500 mg calcium+400 IU vitamin D during the study. BMD was assessed at baseline, 6 months, and 1 year. No significant differences were reported among treatments for BMD.

As evidence suggests a protective effect of vitamin D for asthma exacerbations, the next step is to investigate whether vitamin D supplementation can improve asthma outcomes. Castro et al.¹⁸ evaluated vitamin D supplementation in adult patients on ICS with uncontrolled asthma and vitamin D concentrations <30 ng/mL. This study was the first prospective multicenter trial of vitamin D supplementation. It was a randomized, double-blind, parallel, placebo-controlled trial; 408 patients were assigned to either placebo or one dose of vitamin D₃ 100,000 IUfollowed by 4,000 IU/day for 28 weeks added to inhaled ciclesonide 320 μg/day. The dose of ICS was decreased by 50% twice to 80μg/day if asthma was controlled. The primary end point was the time to the first asthma treatment failure, which was defined as a composite outcome of decline in lung function, use of systemic corticosteroid, healthcare use, and increase in use of β₂-agonist. Eighty-two percent (157/201) of patients on vitamin D₃ supplement achieved a serum 25-OH-VitD concentration >30 ng/mL at 12 weeks, and it was maintained for the duration of the study. The mean serum 25-OH-VitD concentration remained <20 ng/mL in the placebo group. The rate of first treatment failure, overall treatment failure rate, first exacerbation, or overall exacerbation rate did not differ between the treatment groups during 28 weeks of the study. In an exploratory analysis, vitamin D responders (157 patients with 25-OH-VitD >30 ng/mL) had a significantly lower overall rate for asthma treatment failure and exacerbation compared to the placebo group. This finding suggests that a targeted 25-OH-VitD level may be necessary in future trials rather than a fixed dose of vitamin D for all participants. Several small studies of vitamin D supplementation have been conducted in children, but these studies did not have asthma exacerbation as a primary outcome or had enrolled patients with sufficient vitamin D in the study.^19–22

In summary, there is growing body of literature investigating the association between vitamin D and asthma in pediatric and adult patients. It is still not clear what the optimal vitamin D level is for asthma. It is difficult to interpret the results of observational or cross-sectional studies, since the level of vitamin D at the time of exacerbation or lack of asthma controls are not available. The strongest evidence for asthma control and vitamin D seems to be in the pediatric population. In light of recent literature, supplementation with vitamin D in children with insufficient levels seems reasonable. However, well-designed clinical trials are needed to investigate the sufficient level of vitamin D for immune function and vitamin D supplementation (including dose, delivery, and duration) for improvement of asthma outcome in children.

Author Disclosure Statement

No competing financial interests exist.