Introduction: Allergic rhinitis is a common health problem caused by an immune-mediated inflammatory reaction after allergen exposure. It is not a life-threatening condition but severe Allergic Rhinitis has been associated with significant impairments in quality of life, sleep, and work performance. The identification of Vitamin D Receptors in lymphocytes suggested a role for the vitamin in the regulation of immune function. Vitamin D has direct affects on dendritic cells, helper and regulatory T cells and activated B cells. There is increasing evidence linking vitamin D to various immune-related conditions including allergy. This study evaluates the effect of Vitamin D supplementation in allergic rhinitis. Aims and Objectives: To evaluate the levels of Vitamin D in Allergic Rhinitis and its correlation with the severity of disease and the effect Vitamin D supplementation (Cholecalciferol - 1000 IU) on the course of the disease. Material & Methods: Fifty subjects of Allergic Rhinitis were recruited. They were randomised into two groups - Test and Control. Vitamin D levels and Total Nasal Symptom Score (TNSS) were assessed both groups. The test group received oral vitamin D (chole-calciferol; 1000 IU) for thirty days while the Control group received placebo - along with standard medications - for the same period. Vitamin D levels and TNSS were repeated at the end of the study period. Results: Patients of allergic rhinitis showed deficiency in vitamin D indicated by mean vitamin D level of 17.32+8.26 ng/ml in Test group and 18.19+4.66 ng/ml in Control group. The TNSS score was 9.92+1.37 in Test group and 10.17+2.90 in Control group. After the study period, mean vitamin D level was 29.71+2.28 ng/ml in test group and 18.67+4.75 ng/ml in Control group. The Post treatment TNSS scores were 2.81+3.04 in test group and 5.42+7.78 in Control group. This difference between groups was statistically significant. There was significant correlation between the severity of disease as represented by the different TNSS groups and Vitamin D levels. Conclusion: Vitamin D levels were found to be low in subjects with allergic rhinitis. The levels of Vitamin D correlated with the severity of disease. There was significant improvement in the levels of serum vitamin D and highly significant reduction in the total nasal symptom score after supplementation. Thus Vitamin D supplementation alters the course of Allergic Rhinitis towards clinical improvement.
Of the vast majority affected by chronic rhinitis, allergic rhinitis is the commonest type affecting up to 20% subjrcts. Allergic rhinitis has been associated with impaired quality of life, sleep and work performance (1). A number of therapeutic options are available for allergic rhinitis, including antihistamines and topical corticosteroids. The prevalence varies among countries, probably because of geographic and aeroallergen differences (2, 3, 4). In recent times there has been an increase in the incidence and prevalence of this disease. It is estimated that the symptoms of rhinitis are present in 75% of children and 80% of asthmatic adults (5).
Today people are spending more times indoors, leading to less sun exposure and less cutaneous vitamin D production. This has lead to decreasing Vitamin D levels in the population (6). In recent years several studies have suggested that the worldwide increase in allergic diseases is associated with low vitamin D. The association between low serum vitamin D levels and an increase in immune disorders has also been shown (7). While the association of vitamin D in the treatment of asthma have been investigated in several studies, this study evaluates the levels of Vitamin D in patients of Allergic Rhinitis and the effect of oral vitamin D supplementation (Cholecalciferol - 1000 IU) on the course of Allergic Rhinitis.
The study was approved by the Institutional ethical committee. Subjects of allergic rhinitis were screened from the out patient department of our institute. They were between 18 and 60 years of age and of both genders. All screened subjects were subjected to complete clinical history and examination. They then underwent baseline investigations such as complete blood count, chest X ray, LFT, KFT, thyroid function tests, ECG, lipid profile, serum uric acid, and total serum IgE. A total of fifty subjects were recruited for the study. Written informed consent was obtained for the study. Included subjects were those having history of allergic rhinitis along with elevated total serum IgE levels. Subjects with any other systemic illness and those receiving any medications such as oral corticosteroids, calcium or vitamin supplements were excluded.
Subjects were then randomly allocated to two groups – Test Group and Control Group. Serum Vitamin D levels was evaluated in both the groups. Vitamin D was estimated by Enhanced Chemiluminiscence method on Diasorin Liaison analyser using "Liaison 25OH Vitamin D Total" kits. While vitamin D deficiency is defined as 25(OH)D levels < 20ng/ml, vitamin D insufficiency was defined as 25(OH)D levels between 20 to 30 ng/ml (13). Patients with serum vitamin D levels > 30 ng/ml were considered as normal and excluded from the study.
The Total Nasal Symptom Score (TNSS) was also evaluated in both the groups. The TNSS consists of rating of five nasal symptoms (i.e. Rhinorrhoea, Nasal obstruction, Sneezing, Nasal Itching, Anosmia) using four point scale as follows: 0=no symptom evident (Absent), 1= symptom present but not bothersome (Mild), 2= definite symptom that is bothersome but tolerable (Moderate), 3=symptoms that is hard to tolerate (Severe). Each patients total nasal symptoms scores – TNSS were calculated by summing that patients nasal symptoms and scored out of 15 (12).
All subjects in both groups received standard medications in the form of intranasal Azelastine – one spray in both nostrils twice daily. In addition, subjects in the Test group received oral Vitamin D3 (Cholecalciferol; 1000 IU) for 30 days while those in Control group received placebo for 30 days. Serum Vitamin D levels and TNSS scores were obtained after 30 days in both groups. Data were analyzed using SPSSR software (Version 17.0; SPSS, USA).
Of the 50 subjects recruited, two were lost to follow up. Hence analysis was carried out on 23 subjects in the Test group and 25 subjects in the Control group. Of the 23 subjects in the Test group, 12 were male and 11 female with mean age of 31.84+6.55 years. In the Control group there were 13 males and 12 females with mean age of 32.17+7.49 years.
|Serum Vitamin D levels||Test Group||Control Group|
The initial mean vitamin D level was 17.32+8.26 ng/ml in Test group and 18.19+4.66 ng/ml in Control group. Post treatment mean vitamin D level was 29.71+2.28 ng/ml in Test group and 18.67+4.75 ng/ml in Control group (Table 1). The change was significant in the Test group (p=0.015).
|TNSS Scores||Test Group||Control Group|
The mean Vitamin D levels in 86 healthy asymptomatic subjects of both sexes and of all age groups were evaluated. The mean normal value of Vitamin D was 24.74+5.31 ng/ml.
The initial mean TNSS score was 9.92+1.37 in Test group and 10.17+2.90 in Control group. Post treatment scores were 2.81+3.04 in Test group and 5.42+7.78 in Control group (Table 2). The change was found to be highly significant in both the groups (p=0.0001 for Test group and p=0013 for Control group).
|7 - 10||12(47.61%)||2(4.76%)|
|3 - 6||3(4.76%)||6(38.09%)|
|0 - 2||1(9.42%)||15(57.14%)|
In the Test group seven subjects had TNSS>11, twelve has TNSS 7-10, three had TNSS 3-6 and one had TNSS 0-2 in the initial evaluation. Post treatment there were no subjects with TNSS>11, two had TNSS 7-10, six had TNSS 3-6 and fifteen had TNSS 0-2 (Table 3). The mean Vitamin D levels of subjects in the different TNSS groups is depicted in Table 4. The post treatment improvement in TNSS was shown to correlate significantly with the improvement in Vitamin D levels in this group.
|7 - 10||16.71+5.06||27.92+7.39|
|3 - 6||19.18+2.93||28.26+3.56|
|0 - 2||21.08+3.77||30.46+1.88|
Allergic rhinitis is a common health problem caused by an immune-mediated inflammatory reaction after allergen exposure. It is not a life-threatening condition but Severe AR has been associated with significant impairments in quality of life, sleep, and work performance . In the United States, 17-25% of the population, approximately 39 million, is estimated to have allergic rhinitis . The prevalence varies among countries, probably because of geographic and aeroallergen differences [3, 4]. In India, AR is considered to be a trivial disease, despite the fact that symptoms of rhinitis were present in 75% of children and 80% of asthmatic adults .
Allergic diseases are thought to develop due to complex interaction of genetic and environmental factors. Growth in populations has resulted in people spending more times indoors, leading to less sun exposure and less cutaneous vitamin D production . Study by Schauber et al.  implicated that the association between low serum vitamin D levels and an increase in immune disorders is not coincidental. In AR, numerous inflammatory cells, including mast cells, CD4-positive T-cells, B-cells, macrophages, and eosinophils, infiltrate the nasal lining upon exposure to an inciting allergen (most commonly airborne dust mite fecal particles, cockroach residues, animal dander, molds, and pollens) . During the early phase of an immune response to an inciting allergen the mediators and cytokines are released which trigger a further cellular inflammatory response over the next 4-8 h (late phase inflammatory response) which results in recurrent symptoms (usually nasal congestion) . Infiltration of inflammatory cells is evident in both seasonal and perennial form, though the magnitude of these cellular changes is somehow different in seasonal and perennial AR .
The T-cells infiltrating the nasal mucosa are predominantly T helper (Th) 2 in nature and release cytokines (e.g. interleukin [IL] -3, IL-4, IL-5, and IL-13) that promote immunoglobulin E (IgE) production by plasma cells. IgE production, in turn, triggers the release of mediators, such as histamine and leukotrienes, which leads to arteriolar dilation, increased vascular permeability, itching, rhinorrhea (runny nose), mucous secretion, and smooth muscle contraction . Hewison M. showed that Vitamin D regulates the activity of various immune cells, including monocytes, dendritic cells, T and B lymphocytes, as well as immune functions of epithelial cells .
The first scientist who hypothesized a link between nutritional intake of vitamin D and allergies were Wjst and Dold in 1999 . Furthermore, some immune cells express vitamin D-activating enzymes facilitating local conversion of inactive vitamin D into active calcitriol with subsequent paracrine and autocrine effects [13, 14]. Vitamin D inhibits the expression of TLR (Toll-like receptor) on monocytes, inhibits proinflammatory cytokine production, and induces antimicrobial peptide synthesis [15, 16]. Vitamin D also impacts the adaptive immune system, specially affecting T-cell activation and antigen-presenting cells function. In recent studies, vitamin D is associated with reduction of Th1 cytokine secretion and inhibition of T cells proliferation. The association of vitamin D and Th2 cells is less clear and contradictory, with report of both increased and decreased expression of the Th-2 cytokines IL-4, IL-5, and IL-10 in adult peripheral blood cell cultures [17, 18]. So it seems that vitamin D has a key role in Th1-Th2 balance, which could be relevant in allergic disease.
In a study conducted by Hollams et al. in Australia, 689 subjects were seen longitudinally at both ages of 6 and 14 years . This study showed that vitamin D levels at ages 6 and 14 years were predictive of allergy/asthma outcomes at both ages, but more importantly, vitamin D levels at age 6 years were predictive of subsequent atopy and asthma-associated phenotypes at age 14 years. This study showed the association between vitamin D and asthma in older children, comparing with the early-life birth cohort studies.
In this study, patients of allergic rhinitis showed deficiency in vitamin D indicated by mean vitamin D level of 17.32+8.26 ng/ml in Test group and 18.19+4.66 ng/ml in Control group. After supplementation with Cholecalciferol - 1000 IU along with standard medications in the Test group, there was highly significant improvement in the total nasal symptom score and serum Vitamin D levels. In the Control group in which only standard medications were given with placebo, the improvement in the TNSS scores was lower than the Test group and this difference between groups was statistically significant. This improvement may be due to the immunomodulatory effects of Vitamin D.
We found significant improvement in the TNSS scores in both the Test and Control groups. The statistically significant improvement in the symptom scores of subjects on placebo suggests the placebo effect. The placebo effect is a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient's belief in that treatment . Placebo effect has been well studied in many conditions . Evidence of placebo effects derives mainly from two types of experimental research: randomized placebo-controlled clinical trials of drugs and procedures and laboratory experiments specifically aimed at evaluating the placebo effect. Patients in the placebo arm of randomized clinical trials often show substantially improved outcomes relating to symptoms of their disorder as compared with their pretrial baseline . However without comparing a placebo group with a no-treatment control group, a placebo effect cannot be proved. Thus the improvement demonstrated in the TNSS scores of the Control group could be attributed to the placebo effect.
Several other studies show significant deficiency of vitamin-D deficiency in patients of allergic rhinitis compared to general population and thus possibility of causal association. Moradzadeh et al.  in his study showed that the prevalence of severe vitamin D deficiency was significantly greater in patients with AR than the normal population (30% vs. 5.1%; P = 0.03) demonstrating that there is an association between serum vitamin D levels and AR status. A study by Arshi S et al.  showed similar results with prevalence of severe vitamin D deficiency being significantly higher in patients with allergic rhinitis than the normal population, 30% and 5.1% respectively (p = 0.03). Also women with allergic rhinitis had lower vitamin D levels. There has been speculative role of Vitamin-D supplementation in deficient patients with improvement in symptoms of allergic rhinitis. Datt Modh et al.  showed significant clinical improvement in symptom scores compared in the control group in which vitamin D supplements were not given.
There is compelling evidence about the association between low serum vitamin D levels and Allergic Rhinitis. This study also supports this finding. Supplementation of vitamin D in such patients is shown to improve the symptom control of AR. This result suggests the importance of assessing vitamin D levels in patients of allergic rhinitis and suggests the role of vitamin D supplementation therapy along with initial anti allergic treatment in deficient subjects.
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