What evidence is available supporting the use of vitamin D in the treatment of asthma?

Introduction
Asthma is a pulmonary disease defined by limitations in airflow and a variety of respiratory symptoms, such as wheezing and shortness of breath, resulting from chronic airway inflammation.^1,2 Asthma symptoms often present inconsistently from day-to-day and can worsen suddenly in the form of an asthma exacerbation. Although presentation can include a variety of phenotypes based on clinical characteristics, exact pathologies and treatment responses may vary within the same phenotypes. Affecting over 25 million individuals in the United States in 2020, asthma is a highly prevalent disease state with many avenues of ongoing research, particularly in treatment methodologies.³ Current treatments for asthma target symptom control and risk management.^1,2 Symptom control promotes patient comfort and activity by limiting wheezing and other symptoms, whereas risk management aims to lower the future incidence rate of an exacerbation without necessarily impacting symptoms directly. Poor symptom control is a risk factor for asthma exacerbations. Additional risk factors for exacerbations include exposure to allergens or cigarettes, overall lung function, elevated inflammatory markers, and certain chronic medical conditions. Medications can be utilized to alter and alleviate some of these risk factors and to provide symptom management.

Current guideline recommendations for asthma control and risk management involve the use of several types of inhaled medications, most commonly including inhaled corticosteroids (ICS), short-acting beta agonists, long-acting beta agonists, and long-acting muscarinic antagonists.^1,2 Both the National Asthma Education and Prevention Program (NAEPP) and the Global Initiative for Asthma (GINA) guidelines recommend a stepwise approach for treatment based on disease severity and symptom control, recommending treatment escalation for uncontrolled symptoms or increasingly severe disease. Asthma severity is determined clinically by the persistence or worsening of symptoms despite the use of control medications and recommended lifestyle alterations. However, due to improper inhaler technique and other adherence issues, the clinical efficacy of common symptom control medications can be difficult to judge in individual asthma patients. Severe asthma and treatment-resistant asthma have few established alternative treatment options other than escalated therapy for symptom control, and treatment optimization in particular phenotypes is unclear.¹ Additional pharmaceutical options for asthma treatment are therefore being investigated. Inflammation and immunologic processes thought to be involved in asthma pathogenesis are common targets for novel asthma therapy research.^4,5 Vitamin D has demonstrated evidence of immunomodulatory activity and low serum 25-hydroxyvitamin D (25(OH)D) has been associated with impaired pulmonary function, making it a drug of interest in asthma research. The objective of this article is to examine available evidence on the use of vitamin D in the treatment of asthma.

Vitamin D
Vitamin D is a fat-soluble vitamin with vital effects in many biological processes, especially bone health.^6,7 Vitamin D has two primary sources: through synthesis in human skin as ergocalciferol (vitamin D2) or through diet as either vitamin D2 or calciferol (vitamin D3). Both vitamin D2 and vitamin D3 must be metabolized in the liver or extrahepatic tissues into 25(OH)D, which is further metabolized into the steroid hormone 1,25-dihydroxyvitamin D (1,25(OH)2D), the vitamin’s active form.⁶ The recommended daily dose of vitamin D varies by age but is typically between 400 and 800 international units (IU) daily.^6,7 Levels of vitamin D are typically measured by serum concentration of 25(OH)D, although optimal serum concentrations for bone health and overall health have not been conclusively established.^4-7 In general, professional and government organizations recognize that serum 25(OH)D levels less than 50 nmol/L are generally inadequate for bone and overall health and are associated with vitamin D deficiency.^6,7 Older consensus states that serum 25(OH)D levels of 50 nmol/L or more is generally adequate in healthy individuals, while more recent consensus states that a concentration of 75 nmol/L or more is necessary for bone and overall health. Serum 25(OH)D concentrations greater than 150 nmol/L have been determined to be excessive and linked to potential adverse effects. Sufficient levels are typically based on vitamin D’s role in bone homeostasis and might not reflect appropriate vitamin D levels needed for other pathologies or in immunologic health.^4-7

Vitamin D has a well-established role in calcium, phosphorus, and skeletal homeostasis, but has an undefined role in numerous etiologies.^4-7 Vitamin D deficiency has been linked to cancer, type 2 diabetes, and a higher risk of acute infection, among other disease states. Recent evidence suggests that vitamin D has several immunomodulatory effects, including the reduction of inflammatory markers and the regulation of immune cell activity.^4,5 However, while case reports and observational studies of various populations have found an association with vitamin D deficiency and asthma, evidence for vitamin D supplementation in treating asthma has been inconsistent or unclear, leaving clinicians uncertain in their practice.^4,5,8-10

Guidelines
Guidelines for asthma management are conservative in recommending vitamin D. The 2007 NAEPP guidelines recommend considering vitamin D supplementation in adults taking ICS, especially in individuals with osteoporosis risk factors, low bone mineral density, or perimenopausal women.² The 2020 NAEPP update does not mention vitamin D usage in asthma.¹¹ The GINA 2022 updated guidelines provide a limited recommendation to ensure vitamin D sufficiency in women with asthma who are or are planning to become pregnant, as sufficiency may reduce the risk of early-life wheezing in infants.¹ The GINA guideline also acknowledges that low serum 25(OH)D levels in individuals with asthma have been linked to impaired lung function, increased exacerbation frequency, and reduced response to systemic steroids, and that vitamin D supplementation may reduce exacerbations requiring corticosteroids or may improve symptom control in individuals with asthma and a concurrent baseline 25(OH)D less than 25 to 30 nmol/L. However, they do not give any recommendation on vitamin D supplementation in patients with asthma due to the lack of quality evidence.

Efficacy
There have been 3 recent meta-analyses with a goal to elucidate vitamin D’s efficacy in asthma management, each focusing on slightly different topics.^8-10 All 3 included an analysis of vitamin D supplementation on asthma exacerbations as a primary outcome of interest. Select results of each meta-analysis can be found in Table 1.

Li et al (2022) aimed to analyze vitamin D supplementation in allergic diseases during childhood, including in those with asthma.⁸ Following a systematic search, 18 randomized controlled trials (RCTs) focused on vitamin D supplementation versus placebo or control in children with asthma were identified. The primary outcome was the total number of participants with at least 1 asthma exacerbation, and secondary outcomes were related to symptom control and lung function. Analyses demonstrated that vitamin D supplementation did not significantly decrease risk of exacerbations and did not improve symptom control or lung function in children with asthma. However, in a subgroup analysis of children with asthma and severe vitamin D deficiency (baseline serum 25(OH)D <10 ng/mL), vitamin D supplementation significantly reduced the risk of asthma exacerbation compared to control. Only 1 study (n=56) provided data for the severely deficient population, and, due to imprecision of data and a high risk of bias, the quality of the evidence was considered low. This meta-analysis was limited by the heterogeneity seen across trials. Dosage, frequency, and treatment duration varied across trials. Additionally, patient populations differed, and included varying disease severity, varying mean baseline 25(OH)D levels, and varying standards of care. The overall quality of evidence included in the analysis was considered moderate.

Wang et al (2022) published a meta-analysis investigating vitamin D in chronic obstructive pulmonary disease (COPD) and asthma.⁹ A total of 19 RCTs including 2025 patients with asthma investigating vitamin D efficacy were included, with 9 of those studies including children. The primary outcome of participants with at least 1 asthma exacerbation showed no significant difference in vitamin D supplementation and control groups. Of the secondary outcomes analyzed, the ratio of the forced expiratory volume in 1 second (FEV₁) to the forced vital capacity (FVC) of the lungs (FEV₁/FVC) significantly improved from baseline in those taking vitamin D supplementation compared to the control group. However, it is unclear what the clinical significance of this change in FEV₁/FVC could be in patients with asthma. A subgroup analysis of all patients with vitamin D deficiency (baseline serum 25(OH)D ≤ 20 ng/mL), including those with COPD or asthma, revealed a significant increase in interleukin (IL)-10 with vitamin D supplementation, although clinical significance of this change in inflammatory marker is unknown. Definitions of exacerbations and vitamin D sufficiency and deficiency varied across included clinical trials. Additionally, there was no standardized dose or formulation of vitamin D used across RCTs. The meta-analysis authors acknowledged that the treatment effect was heterogeneous across trials and might have been overestimated.

In 2023, Williamson et al updated a Cochrane review of vitamin D for the management of asthma.¹⁰ Studies included in the meta-analysis were placebo controlled, with a minimum duration of 3 months. Eleven new studies were identified and were added to the initial 9 trials used in the prior Cochrane review for analysis. The primary outcome was asthma exacerbation requiring the use of systemic corticosteroids, which was not statistically significantly different between placebo and vitamin D groups. Secondary outcomes, including lung function, symptom control, adverse events, and safety outcomes, also failed to show statistically significant differences between the arms. The evidence analyzed was considered of high quality to assess the primary outcome. Factors such as vitamin D dosage, formulation, and frequency varied across RCTs. Williamson et al explored the potential relevance of several of these factors through subgroup analyses with no statistically significant differences found, although the evidence was often considered low quality. The authors noted that some populations, such as those with severe asthma and those with a baseline serum 25(OH)D of <25 nmol/L, were poorly represented in the included trials and that further studies are needed to determine potential benefit.

These meta-analyses varied in their included trials for analysis due to differing interests in populations and outcomes.^8-10 The Cochrane review by Williamson et al broadly held stricter standards for inclusion and actively excluded several studies analyzed by Li et al and Wang et al. Some trials shared between meta-analyses varied in the authors’ risk of bias evaluation, despite all using the Cochrane bias assessment tool. In evaluation of overlapping RCTs, the risk of bias evaluated by Williamson et al was deemed equal to or higher than in as evaluated by Li et al in almost all cases.^8,10 Every overlapping RCT with a lower risk of bias as evaluated by Williamson et al included unpublished data in its evaluation which Li et al did not specify as part of their risk of bias evaluation. Wang et al described the cumulative risk of bias of all articles included for analysis but did not provide bias evaluations for individually analyzed studies, somewhat obfuscating their justifications for inclusion and exclusion.⁹ Each of these analyses had to contend with the poor standardization in intervention, duration, population, and exacerbation definition within the literature.^8-10 The interventions in these trials varied widely in dosing, formulation, and frequency. Across included trials, participants received 100 IU to 4000 IU vitamin D daily with or without an initial bolus, took daily, weekly, or monthly dosing regimens, and received varying vitamin D formulations. Populations and outcomes were inconsistent, with various definitions of vitamin D deficiency and asthma exacerbation, as well as different inclusion and exclusion criteria for weight, comorbidities, and ages. Each of these additional variables makes any subsequent conclusions regarding vitamin D use in asthma difficult to interpret. Williamson et al were deliberate in defining exacerbations in their analysis and thereby mitigated inconsistencies in the events analyzed across trials.¹⁰

Each meta-analysis ultimately reached similar conclusions regarding vitamin D’s efficacy in decreasing asthma exacerbations: vitamin D shows no significant evidence of efficacy in decreasing exacerbations in asthmatic populations, with the possible exception of severely deficient patients according to Li et al and Williamson et al.^8-10  Points of contrast include Wang et al concluding that vitamin D supplementation significantly reduced the signs of asthma, if not the most severe symptoms, and therefore broadly condoning its use in asthmatic patients due to low risk and low cost, while Williamson et al and Li et al conservatively denied that current data supports vitamin D’s use in the management of asthma and called for further studies in select populations and formulations.

Conclusion
Vitamin D has no strong evidence supporting its use in controlling asthma exacerbations in the typical asthma patient, although potential efficacy in patients with severe asthma or with serum 25(OH)D levels <25 nmol/L is unclear.^8-10 Use of guideline recommended treatments, including ICS and other inhaled medications, should be prioritized in all asthma patients.^1,2 If vitamin D deficiency is documented or if a patient is at high risk for osteoporosis, use of vitamin D supplementation and other appropriate treatments are recommended. However, many uncertainties remain, including the efficacy of supplementation with a goal serum level instead of a universal dose, and the efficacy of various vitamin D formulations.^4,5 The safety of vitamin D is conversely well established, with no documented increase in severe adverse events and very infrequent adverse events attributable to vitamin D supplementation used in the context of asthma.^6,7,10 Based on current evidence, vitamin D supplementation is likely not efficacious for treating asthma, but should be used for treatment of vitamin D deficiency. Further research is warranted to establish if there is efficacy in individuals with severe asthma or those with 25(OH)D levels <25 nmol/L.

References

1. Global strategy for asthma management and prevention. Global Initiative for Asthma. Updated 2022.  Accessed March 17, 2023. https://ginasthma.org/reports/
2. Third Expert Panel on the diagnosis and management of asthma. Guidelines for the diagnosis and management of asthma 2007 (EPR-3). National Heart, Lung, and Blood Institute. Published July 2007. Accessed March 17, 2023. https://www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma
3. Most recent national asthma data. Centers for Disease Control and Prevention. Updated December 13, 2022. Accessed March 17, 2023. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm
4. Salmanpour F, Kian N, Samieefar N, Tabari MAK, Rezaei N. Asthma and vitamin D deficiency: occurrence, immune mechanisms, and new perspectives. J Immunol Res. 2022:6735900. doi:10.1155/2022/6735900
5. Ali NS, Nanji K. A review on the role of vitamin D in asthma. Cureus. 2017;9(5):e1288. doi:10.7759/cureus.1288
6. Nolin TD, Friedman PA. Agents affecting mineral ion homeostasis and bone turnover. In: Brunton LL, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 14th ed. McGraw Hill; 2023:chap 52. Accessed March 17, 2023. https://accessmedicine.mhmedical.com/content.aspx?bookid=3191&sectionid=269726617
7. Vitamin D fact sheet for health professionals. National Institutes of Health. Updated August 12, 2022. Accessed March 17, 2023. Vitamin D – Health Professional Fact Sheet (nih.gov)
8. Li Q, Zhou Q, Zhang G, et al. Vitamin D supplementation and allergic diseases during childhood: a systematic review and meta-analysis. Nutrients. 2022;14(19):3947. doi:10.3390/nu14193947
9. Wang Y, Wang J, Chen L, et al. Efficacy of vitamin D supplementation on COPD and asthma control: a systematic review and meta-analysis. J Glob Health. 2022;12:04100. doi:10.7189/jogh.12.04100
10. Williamson A, Martineau AR, Sheikh A, Jolliffe D, Griffiths CJ. Vitamin D for the management of asthma. Cochrane Database Syst Rev. 2023;2(2):CD011511. doi:10.1002/14651858.CD011511.pub3
11. Cloutier MM, Baptist AP, Blake KV, et al; Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC). 2020 focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020;146(6):1217-1270. doi:10.1016/j.jaci.2020.10.003

Prepared by:
Matthew Kirchoff
PharmD Candidate Class of 2023

Reviewed by:
Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2023

The information presented is current as of March 1, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.