Is vitamin D deficiency important in the natural history of COPD?
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* J K Quint
* J A Wedzicha

*   COPD epidemiology
*   COPD exacerbations
*   COPD mechanisms.

Vitamin D consists of a group of fat-soluble prohormones, the most important of which are vitamin D2 and D3, with measurement of 25-hydroxyvitamin D (25-OHD) closely representing a person's vitamin D2 and D3 status. D2 (ergocalciferol) is plant and fungal derived, while vitamin D3 (cholecalciferol) is made from 7-dehydrocholesterol in the skin. This conversion of 7-dehydrocholesterol to previtamin D3 is governed by both the intensity and appropriate wavelength of the ultraviolet (UV) B irradiation reaching 7-dehydrocholesterol. Adequate amounts of vitamin D3 can be made in the skin after only 10–15 min of sun exposure at least twice a week without sunscreen. However, with longer exposure to UVB rays, equilibrium is achieved in the skin and the vitamin degrades as fast as it is generated. Serum concentrations of vitamin D have been found to vary with age, race, sex, season and geographic location, and subclinical deficiency is common, particularly in temperate climates.1

Once in its physiologically active form vitamin D is released into the circulation, binds to a carrier protein in the plasma (vitamin D-binding protein (DBP)) and is transported to various target organs. The hormonally active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. This VDR is constitutively expressed in monocytes, activated macrophages, dendritic cells, natural killer cells, and T and B cells. Activation has potent antiproliferative, prodifferentiative and immunomodulatory functions; both immune enhancing and immunosuppressive.2 It is these immunomodulatory properties of vitamin D that have particularly attracted interest in recent years with regards to chronic and autoimmune diseases and susceptibility to infection.

Deficiency in vitamin D results from a number of causes, including insufficient intake coupled with inadequate sunlight exposure, from disorders that limit its absorption, hereditary disorders and conditions that impair conversion into active metabolites. For a long time it has been known that deficiency leads to rickets, osteomalacia and osteoporosis, but more recently it has been linked with colon cancer, breast cancer, higher risk of heart attack in men, and an increased risk of infections, for example influenza, tuberculosis (TB) and pneumonia.3 It has even been proposed that in autoimmune disorders vitamin D deficiency arises from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing VDR dysfunction. This VDR dysfunction is thought to cause a decline in innate immune function that increases susceptibility to additional infections contributing to disease progression.4

However, what actually constitutes the degree of vitamin D deficiency, particularly in the context of its immunomodulatory properties, is highly debated. In terms of calcaemic effects, levels <50 nmol/l are probably deficient,3 5 whereas levels may need to be even lower for parathyroid insufficiency. With regards to the immunomodulatory mechanisms of vitamin D it has even been suggested that levels >100 nmol/l are needed for optimal immune functioning.

So does vitamin D deficiency have a role in chronic obstructive pulmonary disease (COPD)? In this issue of *Thorax* (***see page [215](http://thorax.bmj.com/lookup/doi/10.1136/thx.2009.120659)***), Janssens and colleagues report that vitamin D deficiency is more common in patients with COPD, that this deficiency correlates with forced expiratory volume in 1 s (FEV1) and that vitamin D levels decrease with increasing disease severity.6 They have defined deficiency in COPD as levels <20 ng/ml (conversion factor 2.5 for nmol/l). A strong relationship has been shown previously between pulmonary function and serum vitamin D levels independently of a diagnosis of COPD,7 with deficiency associated with lower FEV1. It is difficult to establish the cause and effect in this situation, particularly within the COPD population.

Maternal vitamin D in pregnancy has been associated with asthma symptoms in childhood,8 9 and prenatal vitamin D deficiency is thought to affect fetal lung and immune system development. Thus it is possible that vitamin D deficiency early on in life predisposes individuals to a lower FEV1. Studies in asthma linking low vitamin D levels with disease severity have postulated that the relationship may be secondary to diet and time spent indoors, which in themselves are influenced by a diagnosis of asthma.10 This is also likely to be important in COPD; we know that patients with more severe COPD spend less time outdoors11 and these patients are therefore less likely to be exposed to sunlight and subsequently have lower vitamin D levels. So is vitamin D deficiency just a marker of disease severity rather than a contributing factor? Surely if this is all there is to it, patients with COPD living in the tropics should have milder disease and fewer exacerbations.

The authors also report that genetic variants in the vitamin D-binding gene correlate significantly with vitamin D levels, and suggest that individuals with COPD carrying two T alleles of the rs7041 variant are at particularly high risk for vitamin D deficiency. Other genetic variants in the vitamin D pathway have also been associated with COPD. A single nucleotide polymorphism (SNP) in the DBP has been shown to be protective for COPD,12 and some of the SNPs in the DBP influence circulating vitamin D levels.13 Many polymorphisms also exist in the VDR gene, and the influence of these polymorphisms on VDR protein function may influence immunomodulatory responses.14 To date no study has found a link with VDR polymorphisms and airway infection in COPD, although these polymorphisms have been linked with TB. *Fok*I common variants and *Bsm*I polymorphisms have been associated with muscle strength in COPD.15

Perhaps vitamin D deficiency in COPD is more important with relation to exacerbation risk, and this is how it influences disease severity. We know that exacerbations increase the rate of FEV1 decline,16 so it is possible that those with lower vitamin D levels have more exacerbations and subsequently worse disease. Certainly data are available suggesting that the seasonality of influenza (and possibly other viruses) is related to sunlight exposure and consequently vitamin D levels.17 Viral host defence is complex, involving both innate and acquired immunity; however, we may be closer to establishing markers of viral COPD exacerbations.18 Vitamin D modulates macrophage response by preventing the release of too many cytokines and chemokines,19 20 and it also prevents macrophage maturation.21 22 Multiple studies have linked vitamin D deficiency with TB,23–25 though supplementation studies have shown mixed results.26 27 Several studies have also linked VDR polymorphisms and infection. A study in young Canadian children found the *Fok*I polymorphism to be strongly associated with respiratory syncitial virus (RSV) bronchiolitis.28 Although the f allele encodes a less active VDR and may affect the host's ability to use vitamin D for antimicrobial activities or inflammatory regulation, it has been postulated that higher circulating vitamin D levels could overcome this hypofunctionality. In fact there are several mechanisms by which activated vitamin D binding to the VDR could modulate viral lower respiratory tract disease, including downregulation of the Toll-like receptor 429 to which RSV binds, suppression of T cell proliferation,30 tumour necrosis factor α (TNFα) synthesis29 or stimulation of the production of an antimicrobial host protein.31

Therefore, increasing vitamin D levels into an “optimal range” in COPD may be of benefit on several levels; it may reduce bacterial load at exacerbation and airway bacterial colonisation, influence susceptibility to virus infection or even reduce the rate of FEV1 decline. Certainly as the authors of this article suggest, the next step in establishing the importance of vitamin D deficiency in COPD is to study supplementation in adequately powered clinical trials using relevant clinical outcomes. However, there is much still to be learnt about the role of vitamin D in COPD, and the mechanisms by which increasing vitamin D levels into the normal range would influence the natural history of COPD is far from being determined.

## Footnotes

*   Linked articles [120659](http://thorax.bmj.com/lookup/doi/10.1136/thx.2009.120659).

*   Competing interests None.

*   Provenance and peer review Commissioned; not externally peer reviewed.

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