Chronic obstructive pulmonary disease (COPD) is characterized by a persistent airflow limitation and an abnormal inflammatory response of the airways. COPD is predicted to be the third worldwide cause of mortality by 2020 [
]. Exacerbations in COPD determine disease-associated morbidity and mortality [
]. Patients with frequent exacerbations have a more rapid decline in lung function, worse quality of life and decreased exercise performance. Yet, effective treatment alternatives to prevent exacerbations are still lacking.
Vitamin D deficiency is highly prevalent in patients with COPD [
]. Traditionally, vitamin D is associated with bone health. The discovery of the presence of vitamin D receptors (VDR) in many other cells, such as monocytes, macrophages, muscle cells and endothelial cells, has elicited hypotheses of direct vitamin D effects on these cells. These hypotheses are further strengthened by local 25-hydroxyvitamin D-1-alpha-hydroxylase activity, which converts the inactive 25-hydroxyvitamin D (25(OH)D) to the active 1,25-dihydroxyvitamin D (1,25(OH)
D), in many of these cells. The presence of vitamin D receptors on immune cells [
] and the high prevalence of vitamin D deficiency among COPD patients has given rise to the hypothesis that vitamin D might have a potential effect in preventing exacerbations in patients with COPD [
Vitamin D and the immune system
There is a large body of evidence being generated
to demonstrate that vitamin D influences the innate and adaptive immune system. 1,25(OH)
D is the active form of vitamin D that binds to the VDR, thereby influencing the expression of more than 200 genes. VDR is expressed on a range of immune cells such as macrophages, dendritic cells, and CD4-positive T lymphocytes [
]. In the innate immune system vitamin D modulates Toll-like receptor (TLR)-induced immune responses through inhibition of the NF-κB-pathway and appears to improve antimicrobial defences in general [
]. Vitamin D is capable of inducing endogenous expression of the antimicrobial peptides (AMP) such as cathelicidin. This has been reported in monocytes, macrophages, keratinocytes and in lung epithelial cells [
]. Because AMPs have been found in multiple experimental systems to be essential for defence against a variety of microbial infections, it has been hypothesised that vitamin D can enhance resistance to infections [
]. In addition, vitamin D seems capable of modifying the function of cells classically associated with adaptive immunity whereby activation of VDR downregulates autoimmunity by promoting the differentiation of T-cells into regulatory T-cells [
Vitamin D and pulmonary infections
Vitamin D might influence the development and course of tuberculosis. Patients with low 25(OH)D concentrations have a higher risk of active tuberculosis and vitamin D supplementation may shorten the duration of disease [
]. It is also known that patients with rickets more frequently suffer from airway infections and pneumonia [
]. Several prospective cohort studies in the general population show that lower levels of 25(OH)D are related to increased risk of respiratory infections [
]. A trial with Japanese schoolchildren during the influenza season demonstrated that, compared to placebo, vitamin D supplementation lowered the incidence of influenza A infections [
]. Trials assessing effects of vitamin D supplementation on prevention of respiratory infections in the general adult population have shown conflicting results, which may partly be attributed to differences in prevalence of vitamin D deficiency at baseline and rise of serum 25(OH)D levels during treatments [
Vitamin D and COPD
Patients with COPD are characterised by an abnormal inflammatory response of the airways. Viral and bacterial infections are important triggers of exacerbations and contribute to its progression. Thus, potential effects of vitamin D on the immune system pose an attractive mechanism for the treatment of COPD. Also, in some [
], but not all [
] studies in the general population serum 25(OH)D is positively associated with lung function. Vitamin D deficiency is present in 40–80 % of patients with COPD and is related to disease severity [
]. Recent cohort studies, however, did not show a relationship between 25(OH)D levels and exacerbation rate [
], although these studies had limited statistical power to rule out effects of vitamin D deficiency.
In addition to exacerbations and lung function, skeletal muscle dysfunction in COPD patients contributes to poor exercise capacity, decreased quality of life and increased mortality [
]. In COPD patients, vitamin D deficiency is related to impaired physical performance [
]. In healthy adults, positive effects of vitamin D supplementation have been demonstrated on muscle function and physical performance in particular in older and frail individuals [
RCTs vitamin D supplementation in COPD
Few studies have been performed on the effects of vitamin D supplementation in patients with COPD. In the trial performed by Lehouck et al. [
] vitamin D supplementation did not reduce the incidence of exacerbations. However, in a post-hoc analysis of a subgroup of severely vitamin D deficient patients (25(OH)D concentration < 25 nmol/L), vitamin D supplementation decreased the exacerbation rate. In a very recent multi-center trial by Martineau et al. [
] vitamin D protected against moderate to severe exacerbations in a pre-specified subgroup of vitamin D deficient (25(OH)D concentrations < 50 nmol/L) participants, but not in the study population as a whole.
Two studies have been performed assessing the effect of vitamin D supplementation on physical performance in patients with COPD. A pilot RCT did not show effects of vitamin D supplementation on physical performance, but was limited by the small number of 36 participants and short follow-up of 6 weeks [
]. Also, the study was not specifically aimed at patients with vitamin D deficiency. In the aforementioned RCT by Lehouck et al. a post-hoc subgroup analysis of 50 participants following a rehabilitation programme during the trial was performed [
]. Participants receiving vitamin D supplementation had significantly larger improvements in inspiratory muscle strength and peak exercise tolerance, but not in quadriceps strength and 6-min walking distance. However, this study had limited statistical power and is only applicable for patients following a rehabilitation programme. These findings justify a well-designed RCT to study effects of vitamin D supplementation on muscle strength and physical performance.
Little is known about the total dose and dose interval needed for extra-skeletal effects of vitamin D. In the study of Lehouck et al. [
] participants received a monthly dose of 100.000 IU. In the study of Martineau et al. [
] participants received 120.000 IU every two months. A large dose interval improves compliance but might also cause fluctuating levels of vitamin D metabolites [
]. In two RCTs assessing the effect of vitamin D supplementation on falls and fractures, an increase of fall and/or fracture incidence were shown using annual high dose supplementation [
]. While the mechanism by which vitamin D might cause an increase in falls remains uncertain, several authors suggest it is the dosing interval rather than the total dose that determined these outcomes [
]. These results emphasize the need for an RCT studying a more frequent dosing regimen of vitamin D.
In the present study we aim to study the effects of vitamin D supplementation on exacerbation rate in COPD patients with vitamin D deficiency. In addition, we will also assess the effects of vitamin D on several measures of physical performance. In our trial, we will administer a weekly dosing regimen in contrast to earlier studies, which used larger dosing intervals.