Editorial Open Access
Role of Vitamin D Deficiency in Allergic Diseases: Is this Due to an Impaired Patients’ Response to Corticosteroid Therapy?
Ian Adcock1 and Yassine Amrani2*
1Airways Disease Section, National Heart & Lung Institute Imperial College London, London
2Department of Infection, Immunity and Inflammation, University of Leicester, UK
*Corresponding author: Yassine Amrani, Institute for Lung Health, Department of Respiratory Medicine, Clinical Sciences Building, Glenfield Hospital, Groby Rd, Leicester, LE3 9QP, UK, Tel: +44-116-256-3794; Fax: +44-116-250-2787; E-mail: @
Received: February 13, 2014; Accepted: February 14, 2014; Published: February 17, 2014
Citation: Adcock I, Amrani Y (2014) Role of Vitamin D Deficiency in Allergic Diseases: Is this Due to an Impaired Patients’ Response to Corticosteroid Therapy?. SOJ Immunol 2(1): 3. http://dx.doi.org/10.15226/soji.2014.00111
IntroductionTop
Accumulating evidence now shows that low level of vitamin D is associated with the development and/or aggravation of a number of lung diseases in both adults and children [1-3]. Clinically, low levels of vitamin D refers to hormone deficiency which is defined by a serum level <20ng/mL [4]. Vitamin D insufficiency, typically defined by levels ranging from 20-29ng/mL, has also been regarded as clinically important particularly in children [5]. Despite numerous reports associating vitamin D levels to allergic disorders, the cellular and molecular pathways explaining the protective role of vitamin D in lung diseases have not been fully investigated. The purpose of this short review is to describe the current evidence describing the importance of vitamin D in modulating patient’s response to corticosteroid therapy.
Lower Levels of Vitamin D Correlate with Severity of Allergic Lung Diseases
A number of epidemiological studies from different countries have led to the same conclusion that low levels of vitamin D is associated with asthma in both children and adults. Studies performed in asthmatic children led to the demonstration that vitamin D insufficiency (<30ng/mL) was associated with asthma exacerbations and poor lung function in Puerto Rican patients [6] or poor asthma control and lung function in a British cohort [7]. In contrast, Wu AC, et al. [8] found that vitamin D deficiency rather than insufficiency was a feature in asthmatic children with a poor lung function characterized by a reduced improvement in pre-bronchodilator FEV1 after inhaled corticosteroid treatment over the course of 1 year when compared to hormone sufficient patients [8]. A larger study involving 1024 children with mild-to-moderate persistent asthma from a multicentre clinical trial also found that higher odds of hospitalization and emergency department visits correlate with serum levels of vitamin D below <30ng/mL [9]. A more recent study by Bener A, et al. [10], conducted in Qatari children revealed that vitamin D deficiency was the strongest predicator of asthma although a deficiency in phosphorus or magnesium was also noticed in these patients [10]. In a cohort of Italian children (5-11 year-old), patients with partially controlled or uncontrolled asthma had insufficient levels of vitamin D while those with higher vitamin D levels had their disease well-controlled [11]. In a different study the same group described a poor lung response and >10% FEV1 change in response to exercise challenge in children with intermittent asthma who had vitamin D insufficiency [12]. It is also important to mention that not all studies have found a correlation between low vitamin D levels and severity or the level of asthma control in children [13,14].
In addition to asthmatic children, vitamin D deficiency was also shown to impact on disease severity in adults. In a cohort of non-smoking adults with asthma, Sutherland ER, et al. [15], reported that patients with insufficient levels of vitamin D had increased airway sensitivity to methacholine challenge while patients with higher vitamin D levels had greater lung function [15]. Among the cohort of 121 Costa Rican patients, it was found that 74% of those with a vitamin D insufficiency or 91% of those with a vitamin D deficiency had higher risks of developing a severe disease. In contrast, those with higher levels of vitamin D were protected against the risk of hospitalizations or emergency room visits [16]. A German study involving 280 patients recently confirmed that serum levels of vitamin D <30ng/mL were more prevalent among adult patients with severe and/or uncontrolled asthma and were linked to lower forced expiratory volume in the first one second (FEV1) and sputum eosinophilia [17]. A similar observation linking low levels of vitamin D and poor lung function assessed by air flow limitation was reported in a Chinese cross-sectional study involving 435 patients [18].
Taken together, these epidemiological studies from different parts of the globe reinforced the concept that the lack of vitamin D may have detrimental consequences on the management of asthmatic patients. It has been proposed that this could be due to a loss of the steroid-enhancing anti-inflammatory properties of vitamin D.
Vitamin D and Corticosteroid Therapy in Asthma
The observation that levels of vitamin D were important in determining in vitro corticosteroid responsiveness and steroid requirements in asthmatic children strongly suggested that vitamin D directly or indirectly regulates the therapeutic responses of corticosteroids [19]. A study by Searing and colleagues in asthmatic children showed that patients with low levels of vitamin D not only presented with worse airflow obstruction but also had an increased need for inhaled and oral corticosteroids [20]. In addition, these authors found that combining vitamin D and dexamethasone was effective in inhibiting ex vivo steroid-resistant features such as T cell proliferation, raising the possibility that supplementation with vitamin D could be effective in restoring steroid efficacy.
An earlier study convincingly showed that in the presence of vitamin D, dexamethasone was able to induce secretion of the anti-inflammatory cytokine IL-10 by CD4+ T cells isolated from steroid-insensitive patients. This suggests that vitamin D is able to reinstate corticosteroid responsiveness, at least ex vivo, seen in steroid resistant conditions [21]. The potential role of vitamin D in managing steroid insensitive conditions was further suggested by Nanzer AM, et al. [22]. IL-17 expression is increased in steroid-insensitive asthmatic patients, however, vitamin D treatment suppressed the production of dexamethasone-resistant IL-17 by peripheral blood mononuclear cell (PBMCs) [22]. Furthermore, there was a superior damping of LPS responses of combining vitamin D/dexamethasone compared to individual treatments in PBMCs taken from patients who were either sensitive or resistant to corticosteroid therapy [23].
The greater therapeutic benefit provided by vitamin D/corticosteroid combination could possibly result from an enhanced corticosteroid receptor (GR) signalling. This hypothesis was recently supported by the observation that vitamin D/corticosteroid led to an increased induction of the GR-inducible anti-inflammatory protein called MAPK phosphatase 1 gene [24]. Another interesting anti-inflammatory protein induced by vitamin D/corticosteroid combination is IL-10. A study performed in children defined as severe-therapy resistant asthma reported a positive correlation between systemic levels of vitamin D and levels of IL-10 present in the bronchoalveolar lavage fluids. Although the underlying mechanisms of this association are not known, the authors showed that vitamin D was able to enhance IL-10 production induced by dexamethasone in PBMCs from these patients [25]. The role of IL-10 in the anti-inflammatory action of vitamin D has been previously described by Hawrylowicz CM's group [26-28], which showed that vitamin D significantly increased production of IL-10 by Foxp3+ T regulatory (Treg) cells [26-28]. Interestingly, a positive correlation was also found between serum vitamin D levels and circulating IL-10+Treg cells in asthmatic children [29]. These findings support previous observations made in patients suffering from Crohn’s disease where vitamin D increased IL-10 while inhibiting IFNγ production in CD4+ T cells [30], providing further evidence for its therapeutic potential in managing other inflammatory diseases.
These studies provide undeniable in vitro/ex vivo evidence of a role of vitamin D in regulating corticosteroid responses via mechanisms that remain to be elucidated. The use of vitamin D as therapeutic supplement in asthmatics, therefore, suggested by multiple lines of evidence including that vitamin D inhibits steroid-resistant features and possesses immune-modulatory actions possibly via the regulation of Treg cells. More importantly, vitamin D also exhibits steroid-enhancing properties. These studies raise the interesting possibility that vitamin D supplementation could lead to a better control of asthma, in part by enhancing corticosteroid responsiveness particularly in patients with severe disease.
AcknowledgementsTop
Supported by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR and by Department of Health.
ReferencesTop
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